20th

The Industry’s Preeminent
Event on Novel Drug
Targets and Technologies

Anniversary

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T

on

FINAL AGENDA

TARGET

September 30 - October 3, 2024
Boston, MA | SHERATON BOSTON & VIRTUAL

Conference Programs
September 30

GET

Strategies for Targeting Kinases

Emerging Immune Modulation Strategies

Covalent Chemistries and Induced
Proximity NEW

Synthetic Biology for Drug Discovery
and Therapy NEW

October 1-2

October 2-3

Degraders and Molecular
Glues – Part 1

Degraders and Molecular
Glues – Part 2

Lead Generation Strategies

Target Identification
Strategies

Small Molecules forCancer Targets
Antibodies Against Membrane
Protein Targets
Small Molecules
Targeting RNA
AI/ML-Enabled Drug
Discovery – Part 1

GPCR
Pharmacodynamics:
Kinetics, Allosterism, andBiased Agonism in Pharma
Discovery NEW

Organized byPremierSponsors:

Plenary Keynote
ProgramTARGETon

GPCR-Based Drug
Discovery
Cancer Antibodies
Targeting Transcription
Factors

Discovery ofTransformative
Rx to Treat Obesity and
Related Diseases
Richard DiMarchi, PhD,Distinguished Professor ofChemistry and Chair, Biomolecular
Sciences, Indiana University;
former Executive, Lilly and Novo
Research Labs

AI/ML-Enabled Drug
Discovery – Part 2

Fragment-Based Drug
Discovery for Elusive
Cancer Targets

TRAINING SEMINAR
Drug
Exposure at the Target:
The Role of ADME andPharmacokinetics NEW

Stephen W. Fesik, PhD, Professorof Biochemistry, Pharmacology &Chemistry; Orrin H. Ingram II
Chair in Cancer Research,
Vanderbilt University

Physiologically Relevant
Translational Models

TRAINING SEMINAR

Register bySeptember 6
and Saveup to $300

#BostonDOT24

DiscoveryOnTARGET.com

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About the Event

Discovery on Target (DOT) highlights advances in current andemerging “hot” targets and technologies, as well as target validation
strategies for the discovery and development of novel therapeutic agents
ranging from biologics to small molecules.
We aim to meet your research needs. Visit numerous concurrent sessions
all week for informative presentations, lively dialogue, and meaningfulconnections with peers. Customize your experience further through focused
short courses, training seminars, interactive breakout discussions, andnetworking options that help you engage with experts and solutions providers.

Please use keycode
DOT PDF F when registering!

Our four-day event brings back popular topics like kinases, immunomodulation,and degraders, plus new coverage of covalent chemistries and induced proximity,
synthetic biology, cancer antibodies, generative AI, and translational models.

EVENT AT-A-GLANCEMONDAY
September 30

TUESDAY
October 1#BostonDOT24
WEDNESDAY
October 2

WEDNESDAY
October 2

THURSDAY
October 3

Strategies for Targeting Kinases

Degraders and Molecular Glues – Part 1

Degraders and Molecular Glues – Part 2

Covalent Chemistries and Induced
Proximity NEW

Lead Generation Strategies

Target Identification Strategies

Emerging Immune Modulation
Strategies

Small Molecules for Cancer Targets

GPCR-Based Drug Discovery

Synthetic Biology for Drug Discovery
and Therapy NEW

Antibodies Against Membrane
Protein Targets

Cancer Antibodies

Pre-Conference Dinner Short Courses*
MONDAY, September 30

Small Molecules Targeting RNA

Targeting Transcription Factors

AI/ML-Enabled Drug Discovery – Part 1

AI/ML-Enabled Drug Discovery – Part 2

Physiologically Relevant
Translational Models

Drug Exposure at the Target: The Roleof ADME and Pharmacokinetics NEW

SC1: Protein Degraders: A Focus on PROTACs froman ADME-Tox Perspective
SC2: Fragment-Based Drug Design: Advancing
Tools and Technologies
SC3: DNA-Encoded Libraries
SC4: Best Practices for Targeting GPCRs, Ion Channels, and Transporters with Monoclonal Antibodies
SC5: Developing Physiologically Relevant 3DModels

IN-PERSON ONLY

IN-PERSON ONLYGPCR Pharmacodynamics: Kinetics,
Allosterism, and Biased Agonism in Pharma
Discovery NEW

IN-PERSON ONLY

Pre-Conference Symposium*

Short Course (In-Person Only)*

ConferenceTraining Seminar (In-Person Only)*Premium Package includes access to two short courses and all symposia.
Separate registration required for other packages.

Dinner Short Courses*
WEDNESDAY, October 2
SC6: Protein Degraders: A Focus on PROTACs from a
Beyond Rule of Five Space Perspective
SC7: Chemical Biology for Covalent Discovery,
Phenotypic Screening, and Target Deconvolution
SC8: Biophysical Approaches for GPCRs
SC9: Fundamentals of Generative AI for Drug Discovery
IN-PERSON ONLY

Plenary Keynote Program
WEDNESDAY, October 2

2 | DiscoveryOnTarget.com

Become aSponsor or Exhibitor
SPONSORSHIP PROGRAMS
CHI’s comprehensive sponsorship packages allow you to achieve
your objectives before, during, and long after the event. Maximize
exposure to hard-to-reach decision-makers through the following
sponsorship opportunities:

Podium Presentations - Available within
Main Agenda!

Additional sponsorship & branding
opportunities include:

Showcase your solutions to a guaranteed, targeted audience througha 15- or 30-minute presentation during a specific conference program.
Package includes exhibit space, on-site branding, and access tocooperative marketing efforts by CHI.

•
•
•
•
•

One-on-One Meetings
Work with us to identify your target prospects and we will schedule
meetings for you. Think of us as your inside sales team with all yourhottest leads in close reach. Opportunities sold on a very limited basis.

Invitation-Only Dinner/Hospitality Suite

Meter Boards
Lanyards
Foot Trails
Keynote Chair Drop
Tote Bag Exclusive
Sponsorship

•
•
•
•

Water Bottles
Conference Track
Notebooks
Tote Bag Insert
And more!

For more information regarding exhibit
and sponsorship, please contact:

Sponsors will select their top prospects from the conference
preregistration list for an evening of networking at the hotel or at a choice
local venue. CHI will extend invitations, conduct follow-up, and confirm
attendees. The evening will be customized to meet with yourspecific objectives.

Kristin Skahan
Senior Business Development Manager
781-972-5431
kskahan@healthtech.com

Corporate Support Exhibit Package
Includes 8’x10’ exhibit space. Contact us for more information.

2023 ATTENDEE DEMOGRAPHICS
COMPANY TYPE

65%
17%
5%
4%
3%
3%
1%
1%
1%

n
n
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n
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BiotechPharmaAcademic
Services
CRO
Healthcare
Financial
Government
Societies

LOCATION

72%
17%
7%
4%

n
n
n
n

USA
Asia
EuropeRest of World

US BREAKDOWN
66% n East Coast
26% n West Coast
8% n Midwest

DELEGATE TITLE
25%
23%
22%
19%
7%
2%
2%

n
n
n
n
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Scientist/Technologist
Director
Executive
Sales & Marketing
Professor
ManagernAssistant

DiscoveryOnTarget.com | 3

Thank You to

Our Sponsors
Premier Sponsors:

Corporate Sponsors:

Corporate Support Sponsors:

4 | DiscoveryOnTarget.com

Please use keycode
DOT PDF F when registering!

Plenary Keynote
ProgramJoin colleagues from around the world for the Discovery on Target Plenary Keynote Program. Bridging both halves ofthe event, it’s the only time our whole community of drug discovery professionals assembles together to learn about
big-picture perspectives, innovative technologies, and thought-provoking trends from luminaries in the field.
WEDNESDAY, OCTOBER 2

Discovery of Transformative Rx to Treat Obesity and RelatedDiseases
Richard DiMarchi, PhD, Distinguished Professor of Chemistry and Chair,
Biomolecular Sciences, Indiana University; former Executive, Lilly andNovo Research Labs
Obesity represents a medicinal challenge thatwarrants broad molecular diversity. We havepioneered the recruitment of endogenous
hormones and physiological mechanisms
optimized for pharmacological purposes toaddress it. The discovery of single-molecule,
multi-mechanism incretins enables breakthroughefficacy in lowering body weight. The integrated
pharmacology of these peptides, with endocrine
proteins and nuclear hormones, is providing a library of drug candidates
that promises even greater clinical outcomes and therapy for associateddiseases that have historically proven as intractable to treat as obesity
once constituted.
Professor DiMarchi is a member of the National Academy of Medicine
and the National Inventors Hall of Fame. He is a former Group Vice
President at Lilly and later Novo. His contributions pertain to thediscovery and development of Humalog®, rGlucagon®, Forteo®, andEvista®. His research includes discovery of peptides transforming thetreatment of diabetes and obesity. He is co-inventor on >100 U.S. patents
and co-author to >250 scientific publications. He was identified as a topfive translation researcher by Nature Biotechnology. Since 2003, he has
co-founded eight successful biotech companies.

Fragment-Based Drug Discovery for Elusive Cancer Targets
Stephen W. Fesik, PhD, Professor of Biochemistry, Pharmacology &Chemistry; Orrin H. Ingram II Chair in Cancer Research, Vanderbilt
University
The most highly validated cancer targets (KRAS,
MYC, and WNT) affecting the majority of cancers
are thought to be impossible to drug. Usingfragment-based methods that I pioneered over 25
years ago, we have discovered mutant selective
and pan KRAS inhibitors, potent inhibitors of the
MYC cofactor WDR5, and degraders of b-cateninin the WNT pathway. These novel inhibitors/
degraders should have a tremendous impact on
cancer treatment in the future.
Stephen W. Fesik, PhD is the Orrin H. Ingram II Chair in Cancer Research
and a Professor of Biochemistry, Pharmacology, and Chemistry at
Vanderbilt University School of Medicine. He is also a member of the
Vanderbilt Ingram Cancer Center (VICC), the Vanderbilt Institute ofChemical Biology (VICB), and the Center for Structural Biology (CSB). The
focus of his research is on cancer drug discovery using fragment-based
approaches and structure-based drug design. Prior to joining Vanderbilt
in May 2009, Dr. Fesik was the Divisional Vice President of Cancer
Research at Abbott (2000-2009) where he built a pipeline of compounds
that are showing promising anti-cancer activities in early-stage clinical
trials. In addition, while he was at Abbott, he developed several new NMR
methods, determined the three-dimensional structures of several proteinsand protein/ligand complexes, pioneered a fragment-based method for
drug discovery called SAR by NMR, and applied this method to identify
and optimize ligands for binding to many protein drug targets. Dr. Fesik
has published more than 295 papers, trained 68 postdoctoral fellows,
and has served as a member of the Editorial Boards of many scientificjournals, scientific advisory boards, and the Keystone and Bruker Boardof Directors. He has also obtained several awards, such as the Lifetime
Achievement Award in Nuclear Magnetic Resonance from EAS (2003),
the SBS Technology Innovation Award (2010), the NIH Director's Pioneer
Award (2010), the AACR Award for Outstanding Achievement in Chemistryin Cancer Research (2012), and 2021 Chester Stock Award from Memorial
Sloan Kettering Cancer Center.

In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing participants to exchange ideas and experiencesand develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps
the discussion on track and the group engaged. To get the most out of this format, please come prepared to shareexamples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing.
Please visit DiscoveryOnTarget.com/Interactive-Discussions for a complete listing of topics and descriptions.

DiscoveryOnTarget.com | 5

Dinner Short Courses**Premium Pricing or separate registration required

MONDAY, SEPTEMBER 30 5:00-7:30 PM

SC1: Protein Degraders: A Focus
on PROTACs from an ADME-Tox
Perspective

Instructors:
Prasoon Chaturvedi, PhD, Vice President & Head,DMPK, C4 Therapeutics, Inc.
John Erve, PhD, President, Jerve Scientific
Consulting
This course focuses on proteolysis targeting
chimeras (PROTACs) and will cover topics relevant
to developing them as therapeutics. Topics tobe covered in this part of the course will include
looking at what is known about how PROTACs are
metabolized in vivo and strategies to deliver themwith adequate PK/PD. The unique mechanismof action of PROTACs gives rise to some drug
safety issues not seen in small molecules, which
will be discussed. Finally, we will explore thepossible relevance of circadian rhythm to protein
degradation and PROTACs.

SC2: Fragment-Based Drug Design:
Advancing Tools and Technologies

Instructors:
Daniel A. Erlanson, PhD, Chief Innovation Officer,
Innovation and Discovery, Frontier Medicines
Corporation
Ben J. Davis, PhD, Research Fellow, Biology,
Vernalis R&D Ltd.
This course aims to introduce the fundamentals
of Fragment-Based Lead Discovery (FBLD) toattendees. The first section will focus on theconcepts of using fragments for hit generation.
Special emphasis will be placed on practical
pitfalls and the many ways to advance fragments
to leads and drugs. The second part of the course
will discuss the variety of fragment screening
methods and when they are best applied. The
composition of fragment libraries will also be
discussed in detail. The attendees should comeaway from this course with a solid understandingof what FBLD is and how to apply it.

SC3: DNA-Encoded Libraries

Instructors:
Svetlana Belyanskaya, PhD, former Vice President,
Biology, Anagenex
Ghotas Evindar, PhD, Drug Discovery Consultant,
Former DEL Platform Senior Manager and Group
Leader at GlaxoSmithKline
This course provides an overview of DNA-Encoded
Library (DEL) screening platforms, discusses
common selection strategies for identifying
novel hits from DEL campaigns and delves into
parameters for building a library collection. The
instructors will also cover strategic considerationsin using DEL selection data to accelerate hit-tolead steps in drug discovery.

6 | DiscoveryOnTarget.com

SHORT COURSES AND TRAINING SEMINARS WILL BE OFFERED IN-PERSON ONLY.

SC4: Best Practices for Targeting
GPCRs, Ion Channels, andTransporters with Monoclonal
Antibodies

Instructor:
Joseph Rucker, PhD, Vice President, Research andDevelopment, Integral Molecular, Inc.
Complex membrane proteins represent the
majority of protein classes addressed bytherapeutic drugs. Significant opportunities exist
for targeting complex membrane proteins with
antibodies, but it has been challenging. This course
will examine emerging technologies and strategies
for enabling the successful isolation of specificand functional antibodies against GPCRs, ion
channels, and transporters, and highlight progress
via case studies.

SC5: Developing Physiologically
Relevant 3D Models

Instructors:
Madhu Lal Nag, PhD, CSO, InSpheroNathan P. Coussens, PhD, Scientific Director,
Molecular Pharmacology Laboratory, Frederick
National Laboratory for Cancer ResearchWith the passing of the FDA Modernization Act
2.0, there is a greater interest in the drug discovery
community to develop and use physiologically
relevant in vitro models for drug candidate testing
and IND filings. This course will help attendees
understand what it takes to design and develop
relevant 3D organoid/spheroid models through thevarious stages of assay development, automationcompatibility and data analysis. The utility of thesemodels in answering specific biological questions
and the importance of developing a robust,
scalable 3D model–based assay for preclinicaldecision-making will also be demonstrated throughcase studies.
WEDNESDAY, OCTOBER 2 6:00-8:30 PM

SC6: Protein Degraders: A Focus
on PROTACs from a Beyond Rule ofFive Space Perspective
Instructors:
John Erve, PhD, President, Jerve Scientific
Consulting
Stefanus Steyn, PhD, Research Fellow,
Pharmacokinetics Dynamics & Metabolism, Pfizer
This course focuses on proteolysis targeting
chimeras (PROTACs) and will cover topics
relevant to developing them as oral therapeutics.
Topics to be covered in this part of the course
will include their physicochemical properties andhow these influence solubility and permeability
and assays to determine polarity. We will also
examine ADME topics focusing on in vitro assays
including stability assays, transporters, drug-druginteractions (DDIs), Cytochrome P450 (CYP450)
inhibition, etc.

SC7: Chemical Biology for Covalent
Discovery, Phenotypic Screening,
and Target Deconvolution

Instructors:
Paul Brennan, PhD, Professor, Nuffield Departmentof Medicine, University of Oxford
Brent Martin, PhD, Vice President, Chemical
Biology, Scorpion Therapeutics
Angelo Andres, Senior Scientist, Chemical Biology,
AstraZeneca Pharmaceuticals
This course is designed to provide an overview
and best practices in the use of chemical biology
probes and assays that have been developed for
applications in early drug discovery. Chemists
and biologists working in lead generation, assay
development, phenotypic screening, target
discovery and deconvolution, target engagement
and mechanism-of-action (MoA) studies will all
benefit from attending this course. The instructors
will share their knowledge and expertise aroundthe use of various technologies and chemistries,
and there will be time for open discussion andexchange of ideas.

SC8: Biophysical Approaches for
GPCRs

Instructor:
Matthew T. Eddy, PhD, Assistant Professor,
Chemistry, University of Florida, GainesvilleThis course will cover NMR screening methods formembrane proteins, especially GPCRs; LCP (liquidcubic phase) crystallization applications with afew GPCR examples; and advances in Cryo-EM
and nanodiscs. All these biophysical techniques
will be discussed in the context of their impact onmembrane-protein targeted drug discovery​.

SC9: Fundamentals of Generative AI
for Drug Discovery

Instructors:
Parthiban Srinivasan, PhD, Professor, Data Scienceand Engineering, Indian Institute of Science
Education and Research, Bhopal
Petrina Kamya, PhD, Global Head of AI Platforms,
Vice President Insilico Medicine; President, Insilico
Medicine Canada, Insilico
Deep generative modeling is rapidly transforming
de novo drug discovery, streamlining the entire
process. This course aims to explain the potentialof AI, machine learning, and generative AI models
in creating tailored molecules with specificproperties. It explores the fundamentals of
Variational Autoencoders, Generative Adversarial
Networks, Transformers, Large Language Models(LLMs), BERT, and GPT models in the context ofdrug discovery, highlighting their crucial role inreshaping the pharmaceutical landscape. Alongthe way, we’ll dissect three pivotal techniques forbiopharma specific LLMs: prompt engineering,
retrieval augmented generation (RAG), and finetuning. This course is designed for medicinal
chemists, molecular modeling users, and project
managers seeking to harness the capabilities ofmodern Generative AI concepts and integrate theminto their work.

TRAINING SEMINARS WILL BE OFFERED IN-PERSON ONLY.

Cambridge Healthtech Institute Training Seminars offer real-life case studies, problems encountered and solutions applied, along with extensive coverageof the academic theory and background. Each Training Seminar offers a mix of formal lecture and interactive discussions and activities to maximize
the learning experience. These Training Seminars are led by experienced instructors who will focus on content applicable to your current research andprovide important guidance for those new to their fields.
TUESDAY, OCTOBER 1, 8:00 AM - 6:00 PM | WEDNESDAY,OCTOBER 2, 8:00 - 10:00 AM

TS8A: GPCR Pharmacodynamics: Kinetics,
Allosterism, and Biased Agonism in Pharma Discovery
Instructor:
Terrence P. Kenakin, PhD, Professor, Pharmacology, University of North
Carolina at Chapel Hill
This training seminar describes models and tools that extend GPCR
pharmacology into new therapeutic areas. I review the new datacharacterizing the allosteric nature of GPCRs and how this can be applied
to the discovery of new drugs. Discussion emphasizes characterizationof Biased Agonists, Positive Allosteric Modulators (PAMs), and Negative
Allosteric Modulators (NAMs) in practical terms for application to drug
discovery.

Topics to be Covered:• The Role of Pharmacology in Drug Discovery / Determining Mechanism ofDrug Action / Tools of Pharmacology: Dose-Response Curves, Assays /Pharmacologic Principles: Affinity / Efficacy• What is Efficacy? / The Black/Leff Operational Model / Biased Signaling/ Selecting GPCRs as Drug Targets / Kinetics as a Major Player in GPCR
Drug Selection• Allosteric Protein Function / The 2 Unique Functions of Allosteric
Modulators / ‘Induced-Bias’ and Allosteric Probe Dependence / Quantifying
Allosteric Function / NAMs, PAMs, and PAM-Antagonists / Case Studies:‘Know Your Molecule’

INSTRUCTOR BIOGRAPHY
Beginning his career as a synthetic chemist, Terry
Kenakin received a PhD in Pharmacology at the
University of Alberta in Canada. After a postdoctoral
fellowship at University College London, UK, he joined
Burroughs-Wellcome as an associate scientist for
7 years. From there, he continued working in drug
discovery for 25 years first at Glaxo, Inc., then Glaxo
Wellcome, and finally as a Director at GlaxoSmithKline
Research and Development laboratories at Research Triangle Park,
North Carolina, USA. Dr. Kenakin is now a professor in the Department ofPharmacology, University of North Carolina School of Medicine, Chapel
Hill. Currently he is engaged in studies aimed at the optimal design of drug
activity assays systems, the discovery and testing of allosteric molecules
for therapeutic application, and the quantitative modeling of drug effects. In
addition, he is Director of the Pharmacology graduate courses at the UNC
School of Medicine. He is a member of numerous editorial boards, as well as
Editor-in-Chief of the Journal of Receptors and Signal Transduction. He has
authored numerous articles and has written 10 books on pharmacology.

WEDNESDAY, OCTOBER 2, 1:45 - 5:15 PM | THURSDAY, OCTOBER 3,
8:00 AM - 4:35 PM

TS7B: Drug Exposure at the Target: The Role of ADME
and Pharmacokinetics
Instructor:
Erland Stevens, PhD, James G. Martin Professor, Department of Chemistry,
Davidson College
This training seminar describes how pharmacokinetics (PK) affects drug
exposure at the intended target. The seminar opens with a foundation ofclinical PK including the determination of key PK parameters from Cp-time
data. Seminar materials also cover common preclinical ADME assays thatallow estimation of a compound’s human PK properties. The materials
bridge the idea of a compound’s PK and its observed pharmacodynamic
effects (PD) through coverage of PK/PD modeling. Various drug modalities(e.g., small molecules, antibodies, and peptides) illustrate the concepts ofthe seminar.
Session 1:• Drug discovery—typical order of operations• ADME and key pharmacokinetic parameters• Modeling Cp-time curves from an IV dose
• Modeling Cp-time curves from an oral dose
Session 2:• Oral drug space and membrane permeability• Metabolic stability and intrinsic clearance• Plasma, PPB, and the free drug hypothesis• Compartment modeling and PBPK
Session 3:• Pre-formulation and formulation• Preclinical species and allometric scaling• Non-small molecule drug modalities• PK/PD modeling

INSTRUCTOR BIOGRAPHY
Erland Stevens is formally trained as a syntheticorganic chemist, with a PhD from the Department ofChemistry at the University of Michigan at Ann Arbor.
He specialized in nitrogen heterocycle synthetic
methodology. After completing his postdoctoral
research at The Scripps Research Institute in La Jolla,CA, he joined the chemistry faculty at Davidson College
in Davidson, NC. In addition to teaching organic chemistry, he created anundergraduate medicinal chemistry course and later published a textbook,
Medicinal Chemistry: The Modern Drug Discovery Process, with Pearson
Education. He then created an online medicinal chemistry course, which
has been continuously revised and publicly available for approximately 10
years. He subsequently worked with Novartis to create additional online
materials that are used with employees for continuing education purposes.
He maintains an interest in the computational prediction of pharmacokinetic
parameters based on structural features of drug-like structures.

DiscoveryOnTarget.com | 7

Pre-Conference Symposia*
Cambridge Healthtech Institute’s 15th Annual

Strategies for Targeting Kinases
Novel Chemistries and Techniques for Studying, Modulating, and Degrading Kinases
September 30, 2024
MONDAY, SEPTEMBER 30

8:00 am Pre-Conference Symposium Registration Open and Morning
CoffeeNEW KINASE SCREENS & TARGETS
8:50 Welcome Remarks
8:55 Chairperson’s Remarks
Rui Wu, PhD, Senior Vice President, Head of Research & Preclinical, Chief CMC
Officer, Graviton Bioscience

9:00 Multi-Modal Machine Learning to Screen for Novel,
Conformation-Specific Inhibitors of Dark Kinases
Rayees Rahman, PhD, Co-Founder & CEO, Harmonic Discovery
Dark kinases are a group of 160 proteins with poorly understood biological
functions, resulting in a scarcity of tool compounds that could serveas starting points for drug discovery. We employ a multi-model deeplearning approach to screen for novel inhibitors targeting dark kinases. We
demonstrate that our method identifies molecules that engage these kinases
across various active-site conformational states, thereby broadening the
exploration of the kinase inhibitor chemical space.

9:30 Dark Kinase Allostery Atlas
Dima Kozakov, PhD, Associate Professor, Applied Mathematics & Statistics,
SUNY Stony Brook
The inhibition of kinases has been pursued by the pharmaceutical industry
for over 20 years. We report Dark Kinase Allostery Atlas which is a systematiccollection of binding hot spots located at sites on the entire human kinome,with the focus on dark kinases. The hot spots are identified by FTMap, acomputational analogue of experimental fragment screening. The ensemble issampled by a combination of physics and AlphaFold-based sampling.

10:00 FEATURED PRESENTATION: Targeting Kinase
Scaffolds in Disease

Arvin Dar, PhD, Professor, Chemical Biology, Memorial Sloan
Kettering Cancer Center
I will present structural and in vivo binding data
demonstrating how interactions on wild-type and mutant kinases
impact pathway inhibition and adaptive feedback mediated by reboundsignaling. I will further present structure-based approaches fordeveloping next-generation inhibitors and molecular glues with the goalof improving target engagement and combinatorial activity to mitigate
the emergence of drug resistance.

10:30 Pocket-Specific Fragment Hits for RIPK1 andtheir Evolution into Long Residence Time Inhibitors
Lars Neumann, Co-Head - Discovery Solutions, Proteros Biostructures GmbH
Proteros offers generation of Qualified Hits for challenging targets to enable
demanding drug discovery projects. We present the identification of pocketspecific fragments for RIPK1 and their development into long residence time
inhibitors as performed for the UT MD Anderson Center. A Proteros fragment
library was screened with site-specific binding assay techniques, hits werekinetically profiled and binding modes were verified by protein crystallography
all in-house.

11:00 Enjoy Lunch on Your Own

8 | DiscoveryOnTarget.com

NOVEL KINASE MODULATORS
12:25 pm Chairperson’s Remarks
Ken Hsu, PhD, Stephen F. and Fay Evans Martin Endowed Associate Professor,
Department of Chemistry, The University of Texas at Austin

12:30 Nephroprotective Effects of a ROCK2 Inhibitor in Model ofHypertension-Accelerated Chronic and Diabetic Kidney Disease
Rui Wu, PhD, Senior Vice President, Head of Research & Preclinical, Chief CMC
Officer, Graviton Bioscience
Graviton’s GV101 is a potent, selective and best-in-class ROCK2 inhibitor.
Our data in a hypertension-accelerated animal model demonstrate that
GV101 treatment improves insulin sensitivity and reduces the plasma
glucose and HbA1c levels. GV101 also reversed kidney fibrosis, especiallyglomerulosclerosis. This was illustrated with AI-powered pathological analysis
of PAS-stained kidney sections. In addition, GV101 reduced macrophage
infiltration and prevented the buildup of kidney injury molecules.

1:00 Allosteric Modulation of NEK7 to Inhibit the NLRP3Inflammasome
David Bearss, PhD, Co-Founder & CEO, Halia Therapeutics
We have developed a groundbreaking approach by identifying a new
allosteric modulation mechanism of NEK7. This modulation interrupts
the vital interaction between NEK7 and NLRP3, effectively preventing theformation and function of the NLRP3 inflammasome, a major contributor to
inflammatory and autoimmune diseases. These findings present a promisingtherapeutic strategy for effectively managing complex immune responses andinflammation.

1:30 Discovery of Novel Degrader Targeting PTK6 KinaseIndependent Functions
Yan Xiong, PhD, Instructor, Laboratory of Dr. Jian Jin, Pharmacological
Sciences, Icahn School of Medicine at Mount Sinai
PTK6/Brk was reported as an oncogenic driver in several tumor types and insome cancer types; PTK6 non-catalytic functions play key roles in oncogenic
activities. We present the discovery of novel PROTAC degrader, MS105, which
potently downregulates PTK6 level, induces expression of Bim, and apoptosisof cancer cells. Taken together, our studies suggest PTK6 degrader could
provide a preferred approach to clinically targeting PTK6 in cancer.

2:00 In-Person Brainstorming Session

This informal session will be led by the speakers, allowing participants
to ask questions and exchange ideas around topics related to thesymposium. To get the most out of this session, please come prepared
to share your ideas and participate in collective problem-solving.

2:45 Networking Refreshment Break
3:15 Covalent Strategies for Targeting the Kinome
Ken Hsu, PhD, Stephen F. and Fay Evans Martin Endowed Associate Professor,
Department of Chemistry, The University of Texas at Austin
I will describe the synthesis of sulfonyl-triazoles as a new phenol-reactive
group for covalent modification of tyrosine and lysine residues on proteinsthrough sulfur-triazole exchange (SuTEx) chemistry. The reactivity of SuTEx
chemistry is highly tunable, which can facilitate optimization of potent andselective binders to orthosteric and allosteric sites on kinases. I will conclude
my talk by describing efforts to use lead SuTEx inhibitors for modulating
kinase function in cells.

*Premium Package includes access to two short courses and all symposia.
Separate registration required for other packages.

Pre-Conference Symposia*
Cambridge Healthtech Institute’s 15th Annual

Strategies for Targeting Kinases
Novel Chemistries and Techniques for Studying, Modulating, and Degrading Kinases
September 30, 2024
3:45 E3 Warhead Meets Small Molecule: Evaluating Kinome Binding
between Therapeutic Modalities with Reverse Competition
Fiona Pachl, PhD, Associate Principal Scientist, Chemical Biology andProteomics, AstraZeneca Pharmaceuticals
Proteolysis-targeting chimeras (PROTACs) offer the ability to drive
degradation of kinases more selectively and efficaciously, relative toconventional small molecules. Discerning compound engagement with thekinome is challenging due to low expression levels of kinases but is necessary
to compare the effects of PROTACs to corresponding small molecules. We
present a kinase enrichment strategy implementing reverse competition todifferentiate between small molecule binding and PROTAC binding on thekinome.

4:15 Close of Symposium
5:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

7:30 Close of Day

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Pre-Conference Symposia*

NEW

Cambridge Healthtech Institute’s Inaugural

Covalent Chemistries and Induced Proximity
Strategies to Modulate Cellular Interactions and Drive New Therapies
September 30, 2024

NOVEL APPROACHES FOR INDUCING PROXIMITYMONDAY, SEPTEMBER 30

8:00 am Pre-Conference Symposium Registration Open and Morning
CoffeeEMERGING COVALENT STRATEGIES
8:50 Welcome Remarks
8:55 Chairperson’s Remarks
Kay Ahn, PhD, CSO & Co-Founder, ReAx Biotechnologies

9:00 Covalent Drug Discovery Strategies to Tackle Challenging
Cancer Targets
Brent Martin, PhD, Vice President, Chemical Biology, Scorpion Therapeutics
Recent chemoproteomics advances have enabled covalent ligand discovery
across a broad range of new targets. Here, we discuss the expanding role ofchemical biology and chemoproteomics to support covalent lead discovery
efforts, from early hit-finding to late lead optimization.

9:30 Discovery, Optimization, and Characterization of a Covalent
Small Molecule Inhibitor against an Anti-Apoptotic Protein Target
Brooke Brauer, PhD, Senior Research Scientist, Mass Spectrometry,
AstraZeneca Pharmaceuticals
In this talk, I will discuss the biochemical and biophysical assays used to
optimize and characterize a covalent small molecule inhibitor against an
anti-apoptotic protein. I will then discuss how targeted proteomics wasused to monitor the impact of compound treatment on target half-life and to
determine target occupancy.

10:00 Chemoproteomic Profiling in Multiple Cell Types to Assess
Pharmacological Targets and Off-Target Safety Risks
Doug Johnson, PhD, Senior Director, Chemical Biology & Proteomics, Biogen
This presentation will describe our utilization of clickable chemical biology
probes to assess target engagement and conduct selectivity profiling to
identify off-targets in two drug discovery endeavors featuring covalent
inhibitors. In both instances, thorough selectivity profiling across multiple
cell types was pivotal, allowing for a more comprehensive identification ofpotential off-targets that could pose safety concerns.

10:30 Kinetic Profiling of Covalent Inhibitors using
COVALfinder®
Patricia Alfonso San-Segundo, Co Founder & CSO, Enzymlogic
We will present case studies illustrating how Enzymlogic’s COVALfinder
platform provides a detailed understanding of inactivation kinetic parameters
KI, kinact, kinact/KI, T1/2∞ for determination of Kinetic Selectivity in covalent
drug design. Enzymlogic serves an international client base with kinetic
screening of reversible & irreversible inhibitors in early discovery to iterate
Medicinal Chemistry, understand PK PD disconnects and build better models
to define therapeutic windows.

11:00 Enjoy Lunch on Your Own

12:25 pm Chairperson’s Remarks
Philip E. Brandish, PhD, Senior Vice President, Immuno-Oncology, Bicycle
Therapeutics

12:30 Constrained Bicyclic Peptide Conjugates as Novel
Therapeutics in Cancer
Philip E. Brandish, PhD, Senior Vice President, Immuno-Oncology, Bicycle
Therapeutics
Constrained bicyclic peptides that embody the minimal pharmacophore ofan antibody without the protein scaffold are well-suited to induced proximity
applications because of their small size, high ligand efficiency, and ease of
conjugation. At Bicycle Therapeutics, we are exploring how conjugation of
Bicycle molecules to afford simultaneous binding and pharmacology at morethan one target or site can access novel biology and lead to impactful new
medicines.

1:00 Strategies to Chemically Control Protein Stability and Activity
Behnam Nabet, PhD, Assistant Professor, Human Biology Division, Fred
Hutchinson Cancer Center
Small molecules that chemically induce proximity are powerful approaches torewire the circuitry of the cell. My talk will describe our recent advances in thedevelopment of chemical-genetic tag-based platforms to precisely modulate
protein levels, stability, and activity. I will also describe our work to apply theseapproaches for biological investigation and pre-clinical target discovery andvalidation.

1:30 Covalent Proximity-Induction Strategies to Modulate LigandReceptor Interactions for Immuno-Oncology
Anthony Rullo, PhD, Associate Professor, Department of Medicine, Chemistry
and Chemical Biology, McMaster University
A major class of tumor immunotherapeutics function by bridging immune
machinery with tumor antigens, highly expressed on cancer cells compared tonormal tissue. In this talk, we describe the development of chimeric moleculesthat use covalency to induce cell-cell proximity. Covalent stabilization of
ternary complexes significantly enhances tumoricidal immune function, andmay find special utility for induced proximity in the absence of positive cooperativity.

2:00 In-Person Brainstorming Session

This informal session will be led by the speakers, allowing participants
to ask questions and exchange ideas around topics related to thesymposium. To get the most out of this session, please come prepared
to share your ideas and participate in collective problem-solving.

2:45 Networking Refreshment Break
3:15 Specific Covalent Targeting of Histidine, Tyrosine, and Lysine
to Expand the Druggable Proteome
Andrea Zuhl, PhD, Vice President, Chemical Biology & Proteomics, Hyku
Biosciences, Inc.
The integration of covalent chemistry with chemoproteomics has catalyzed
the identification of novel small molecule binding pockets across theproteome. This talk will describe key features of the HYKU platform including
warhead development for covalent screening of histidine, tyrosine, and lysine*Premium Package includes access to two short courses and all symposia. Separate
registration required for other packages.

DiscoveryOnTarget.com | 10

Pre-Conference Symposia*

NEW

Cambridge Healthtech Institute’s Inaugural

Covalent Chemistries and Induced Proximity
Strategies to Modulate Cellular Interactions and Drive New Therapies
September 30, 2024
(HYK) residues; optimizing mass spectrometry-based chemoproteomics
for non-cysteine amino acids; and integration of structural information toprioritize novel binding pockets for further development of covalent or noncovalent compounds.

3:45 Mini-PROTACsHai Rao, PhD, Professor and Chair, Department of Biochemistry, Southern
University of Science and Technology, China
Proteolysis-targeting chimera (PROTAC) that selectively eliminates
detrimental proteins represents a promising therapeutic strategy forvarious diseases. We have developed a set of PROTACs with the short andinterchangeable degradation signals that attract several distinct E3 ubiquitin
ligases. We demonstrate the utility and efficacy of these mini-PROTACs invitro and in vivo, expanding the repertoire of limited ligands and degradation
pathways available for PROTACs.

4:15 Close of Symposium
5:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

7:30 Close of Day

DiscoveryOnTarget.com | 11Pre-Conference Symposia*
Cambridge Healthtech Institute’s 3rd Annual

Emerging Immune Modulation Strategies
Assays and Techniques for Identifying, Understanding, and Predicting Immune Responses
September 30, 2024
MONDAY, SEPTEMBER 30

8:00 am Pre-Conference Symposium Registration Open and Morning
CoffeeEXPLORING DIVERSE MODALITIES
8:50 Welcome Remarks
8:55 Chairperson’s Remarks
Rakesh Dixit, PhD, DABT, President & Founder, Bionavigen Oncology, LLC andRegio Biosciences

9:00 Challenges and Opportunities in the Development of AntibodyImmune Agonist Conjugates (AIC)
Rakesh Dixit, PhD, DABT, President & Founder, Bionavigen Oncology, LLC andRegio Biosciences
AICs are a new generation of tumor antigen-targeting antibody-immune
agonists conjugates that stimulate innate and adaptive immunity, providing
dual therapeutic MOAs in eliminating cancers. While providing great promises,
many early AICs were terminated in clinical development due to poorly
manageable toxicities, immunogenicity, poor PK, and limited clinical efficacy.
The presentation will comprehensively review ISACs’ composition andfunction, lessons learned from failed AICs, and opportunities of developing thenext generation of AICs.

9:30 Bivalent Agonist Antibodies as a Next-Generation
Immunological Platform
Andy Sullivan, MS, Associate Director, Biology and Pharmacology, Diagonal
Therapeutics
The use of cytokine muteins to target and activate the immune system is apromising approach to treating cancer, but several challenges are affecting its
applicability—as the discovery process can be time-consuming and restrictive
due to the limitations of the natural cytokine. Bivalent agonist antibodies
possess distinct developability features that present the opportunity toselectively address unmet needs that were not druggable with conventional
muteins.

10:00 Anti-Tumor Immunity Induced by Precision-Guided Bicycle
Therapeutics
Anne-Sophie Dugast, PhD, Director Oncology, Discovery Research, Bicycle
Therapeutics
Small bicyclic peptides constrained by a central scaffold can havepharmacologic and pharmacodynamic properties that fit very well withthe design goals and are therefore ideally positioned to deliver immune
agonists in a way not practically feasible with traditional antibodies. We will
demonstrate that Bicycle TICAs (tumor-targeted immune cell agonists) canpotently activate anti-tumor immunity in cancer, in particular via the activating
receptors CD137 and NKp46 in a tumor-targeted manner.

10:30 Sponsored Presentation (Opportunity Available)
11:00 Enjoy Lunch on Your Own

TARGETING TUMOR CELLSPeng Wu, PhD, Professor, Chemical Physiology, Scripps Research Institute
Adoptive cell transfer therapy is a new paradigm in cancer treatment.
However, during the ex vivo expansion process, T cells undergo exhaustion—
as a result they lose the ability to persist after adoptive transfer. In this talk,I will discuss small molecule modulators discovered in my lab which canfacilitate T cell proliferation and generate T cells with stem cell-like properties.
Upon transfer, they confer excellent tumor control.

1:00 RNAi Conjugates for Cancer Immunotherapy
Shanthi Ganesh, PhD Director, Pharmacology, Global Nucleic Acid Therapies,
Novo Nordisk
Refractory malignant solid tumors create an immunosuppressive tumor
microenvironment (TME), which renders them resistant to standard-of-care
immune checkpoint inhibitors. We developed RNAi agents to silence STAT3
or PD-L1 targets in tumor-associated immune cells, which mediate immune
suppression in the TME. Silencing these genes remodeled the TME andincreased cytotoxic T-cell infiltration into the tumor. Human active STAT3 andPDL1 RNAi conjugates are currently in Phase 1 trials for immunotherapyrefractory cancers.

1:30 Precision Immunotherapy for Oncogenic Driver Mutations
Gary Shapiro, PhD, VP, Discovery Biology, Affini-T Therapeutics Inc.
Affini-T, a precision immunotherapy company, develops potentially curative
therapies for solid tumors by targeting oncogenic driver mutations, beginningwith KRAS. We are advancing two distinct therapeutic modalities, adoptive
cellular therapies and bispecific T cell engagers, designed to harness T cell
immunity with unprecedented precision and potency. Our TCR-T cell therapyenabling platforms utilize state-of-the-art TCR discovery, synthetic biology,
and gene editing to modify the tumor microenvironment and optimize T cellfunctions.

2:00 In-Person Brainstorming Session

This informal session will be led by the speakers, allowing participants
to ask questions and exchange ideas around topics related to thesymposium. To get the most out of this session, please come prepared
to share your ideas and participate in collective problem-solving.

2:45 Networking Refreshment BreakTOOLS FOR IMMUNE MODULATION
3:15 Analysis Platforms to Quantify Tumor-Immune Interactions
through Multiplexed Spatial Profiling Technologies
Arvind Rao, PhD, Associate Professor, Department of Computational Medicine
and Bioinformatics, University of Michigan
Spatial profiling technologies have the potential to enable multi-factorial,
multi-modal characterization of the tissue microenvironment. Scalable,
quantitative methods to analyze and interpret spatial patterns of protein
staining and gene expression are required to understand cell-cell relationships
in the context of local variations in tissue structure. We will discuss elementsof spatial profiling from multiple studies as well as paradigms from statistics
and machine learning in the context of these problems.

3:45 Developing and Applying a Novel Chemoproteomics Platform
for Immune Cell Transcription Factors

12:25 pm Chairperson’s Remarks
Peng Wu, PhD, Professor, Chemical Physiology, Scripps Research Institute12 | DiscoveryOnTarget.com

12:30 Developing Small-Molecule Modulators to Alleviate T Cell
Exhaustion

Olesya Ulanovskaya, PhD, Senior Director, Biology, Belharra Therapeutics
Belharra Therapeutics is the next wave in chemoproteomics focusedon applying a novel chemistry enabled non-covalent probe library andquantitative mass spectrometry to identify chemical probes that selectively*Premium Package includes access to two short courses and all symposia. Separate
registration required for other packages.

Pre-Conference Symposia*
Cambridge Healthtech Institute’s 3rd Annual

Emerging Immune Modulation Strategies
Assays and Techniques for Identifying, Understanding, and Predicting Immune Responses
September 30, 2024bind any pocket, on any protein, in live cells. Most proteins identified as
being selectively engaged by our probe library do not have a reported ligand,demonstrating the ability to identify novel pockets and potential chemicalprobe starting points for these targets.

4:15 Close of Symposium
5:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

7:30 Close of Day

DiscoveryOnTarget.com | 13

Pre-Conference Symposia*

NEW

Cambridge Healthtech Institute’s Inaugural

Synthetic Biology for Drug Discovery and Therapy
Novel Cellular Engineering and Predictive Modeling for Regulating Diverse Systems
September 30, 2024
MONDAY, SEPTEMBER 30

8:00 am Pre-Conference Symposium Registration Open and Morning
Coffee8:50 Welcome Remarks
8:55 Chairperson’s Remarks
Ron Weiss, PhD, Professor, Biological Engineering, Massachusetts Institute ofTechnology

9:00 FEATURED PRESENTATION: Mammalian
Synthetic Biology and Programmable Organoids

Ron Weiss, PhD, Professor, Biological Engineering,
Massachusetts Institute of Technology
Programmable Organoids is a new platform for drug
discovery that enables rapid and effective drug screening. Based onprogrammed differentiation into synthetic mammalian tissues having
multiple cell type architectures similar to human organs, Programmable
Organoids mimic the response of a target organ to both positive andnegative effects of drug candidates. Organoids programmed with bothgeneral and disease-specific sensors can be used to identify candidates
for further analysis.

10:00 Programming mRNA for Cancer Immunotherapy
Jaspreet Khurana, PhD, Senior Director, mRNA Programming, Strand
Therapeutics Inc.
We have developed a platform in which we design RNA-encoded
programmable genetic “circuits” that detect molecular cues in a cell to
specifically express a payload protein in cells that exhibit a particularmolecular signature. We applied this platform to the development ofour program which entails systemic delivery of lipid nanoparticle (LNP)encapsulated mRNA-bearing programmable genetic circuitry that selectively
expresses a therapeutic payload within target cells.

10:30 Protein-in-hand in 48 hours: Multiplexing Protein
Expression and Purification Screen on a Digital
Microfluidic Device
Michael Chen, CEO & Co Founder, Nuclera UK
The eProtein Discovery™ System can screen multiple protein expression andpurification profiles and deliver reliable proteins in-hand in less than 48 hours.
eProtein Discovery reduces the timelines and costs associated with protein
production through 24 customizable expression conditions and subsequentidentification of optimal conditions for scale-up. Integrating cell-free protein
synthesis and digital microfluidics on smart cartridges, Nuclera’s eProtein
Discovery enables rapid access to even challenging proteins at high quality.

11:00 Enjoy Lunch on Your Own

PROGRAMMING CELLULAR PATHWAYS
12:25 pm Chairperson’s Remarks
Akos Nyerges, PhD, Research Fellow, Laboratory of Dr. George Church,
Department of Genetics, Harvard Medical School

12:30 Programming Mammalian Gene Expression with Synthetic
Promoters
William Chen, MD, PhD, Assistant Professor, Sanford School of Medicine,
University of South Dakota
Constitutive mammalian gene expression relies on a limited collection ofnatural promoters that drive discrete levels of transcription. The activities
of many natural promoters are unpredictable in different species and cell
types, making it difficult to precisely control transgene expression. To
address these obstacles, using synthetic biology toolkits, we have developed
versatile, scalable synthetic promoter platforms and programmable genetic
components to transform the regulation of mammalian transcription andtransgene expression.

1:00 Synthetic Gene Circuits for Cancer Immunotherapy: Turning
Cancer Cells against Themselves
Ming-Ru Wu, MD, PhD, Assistant Professor, Department of Cancer Immunology
and Virology, Dana-Farber Cancer Institute, Harvard Medical School
We have developed synthetic cancer-targeting gene circuits that specificallytarget cancer cells. Once the circuits enter cells, they will sense the activityof several cancer-associated transcription factors and get activated in tumor
cells to trigger tumor-localized combinatorial immunotherapy. Circuits
mediate robust therapeutic efficacy in ovarian cancer mouse models. This
platform can be adjusted to treat multiple cancer types and can potentiallytrigger any genetically-encodable immunomodulators as therapeutic outputs.

1:30 Talk Title to be Announced
Farren Isaacs, PhD, Professor, Department of Molecular & Cellular &Developmental Biology, Yale University

2:00 In-Person Brainstorming Session

This informal session will be led by the speakers, allowing participants
to ask questions and exchange ideas around topics related to thesymposium. To get the most out of this session, please come prepared
to share your ideas and participate in collective problem-solving.

2:45 Networking Refreshment Break
3:15 Engineering High-Precision, Dynamic Genetic Control Systems
for Cellular Engineering
Katie Galloway, PhD, W. M. Keck Career Development Professor, Biomedical
Engineering and Chemical Engineering, Massachusetts Institute of Technology
Integrating synthetic circuitry into larger transcriptional networks to mediate
predictable cellular behaviors remains a challenge. To accelerate highefficiency cellular engineering, we’ve developed physiochemical models ofgene regulation to guide the design of highly-compact genetic tools withimproved performance across cell lines and primary cells. In this talk, I
will share how these models have improved engineered cells and opened
opportunities for phenotypic screening, disease modeling, and gene and celltherapies.

3:45 Multiplexed in vivo Screening of Tissue-Specific Targeting
Protein Therapies
Alex Reis, PhD, Principal Scientist, Computation, Manifold Biotechnologies Inc.
Manifold has developed an in vivo protein multiplexing platform, using aproprietary protein barcoding technology (mCodes), and is now leveraging it
to engineer tissue-specific biologics with optimal profiles. We share several
case studies using our platform across diverse therapeutic areas, including*Premium Package includes access to two short courses and all symposia. Separate
registration required for other packages.

DiscoveryOnTarget.com | 14

Pre-Conference Symposia*

NEW

Cambridge Healthtech Institute’s Inaugural

Synthetic Biology for Drug Discovery and Therapy
Novel Cellular Engineering and Predictive Modeling for Regulating Diverse Systems
September 30, 2024
neuro and metabolic disease. We have applied this platform to screen 1000sof shuttle candidates in vivo, resulting in shuttles against novel receptors forbrain and tissue uptake.

4:15 Close of Symposium
5:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

7:30 Close of Day

DiscoveryOnTarget.com | 15

Cambridge Healthtech Institute’s 6th Annual

Degraders and Molecular Glues – Part 1
Design and Optimization of Novel Degraders and Glues | OCTOBER 1-2, 2024

TUESDAY, OCTOBER 1

7:00 am Registration Open and Morning Coffee

STRUCTURAL & MECHANISTIC CHARACTERIZATION
7:55 Welcome Remarks
8:00 Chairperson’s Remarks
Ralph Mazitschek, PhD, Assistant Professor, Harvard Medical School;
Co-Director of the Chemical Biology Platform, Center for Systems Biology,
Massachusetts General Hospital

8:05 CoraFluor-Enabled TR-FRET Assay Strategies for Facile
PROTAC Profiling
Ralph Mazitschek, PhD, Assistant Professor, Harvard Medical School;
Co-Director of the Chemical Biology Platform, Center for Systems Biology,
Massachusetts General Hospital
Building on our CoraFluor TR-FFRET technology, we have establisheda versatile assay platform for the comprehensive characterization of
PROTACs and molecular glue degraders, including (a) detailed kinetic
and thermodynamic analyses of ligand binding to both endogenous andrecombinant proteins, (b) accurate quantification of ternary complex
cooperativity, (c) facile measurements of cellular protein levels. Thisadvancement provides a robust toolset for enhancing the understanding anddevelopment of targeted protein degradation technologies.

8:35 Leveraging High-Throughput Targeted Proteomics to Impact a
Protein Degrader

neurodegeneration. Discovery and development of molecular glue for parkinubiquitin ligase that induces mitophagy and improves neuronal health will be
discussed.

10:35 Preclinical Characterization of a Selective and CNS-Penetrant
BTK Degrader
Bekim Bajrami, PhD, Senior Scientist, Chemical Biology and Proteomics,
Biogen, Inc.
Multiple sclerosis (MS) is characterized by inflammation and demyelinationin the central nervous system, lacking effective treatments despiteadvancements. Bruton’s tyrosine kinase (BTK) is crucial in B cell activationand MS autoimmunity. BTK degraders offer a fresh therapeutic path by
specifically degrading BTK protein. This talk discusses the rationale fortargeting BTK in MS and elucidates the mechanism of BTK degraders throughpreclinical characterization of selective and CNS-penetrant degraders.

11:05 Small Molecule Lysosome-Targeting Chimeras (SMaLTACs):
Receptor Mimetics Targeting Extracellular Proteins for Degradation
Angelo Andres, Senior Scientist, Chemical Biology, AstraZeneca
Pharmaceuticals
The targeted degradation of extracellular and membrane proteins via
lysosome targeting chimeras (LYTACs) requires the engineering of bispecifics
or targeting antibodies functionalized with multivalent carbohydrates todeliver targets for degradation. We have developed a small molecule-based
platform termed small molecule lysosome targeting chimeras (SMaLTACs).
Using a modular chemical approach we demonstrate how SMaLTACs are
rapidly deployed to degrade cell surface receptors and they may how compare
mechanistically to existing approaches.

Wankyu Lee, PhD, Senior Research Scientist, AstraZeneca Pharmaceuticals
Targeted proteomics through parallel reaction monitoring (PRM) leverages
high precision and quantitative accuracy for target protein(s), affording higher
throughput as opposed to discovery proteomics. For degrader projects,
targeted proteomics is invaluable for quantitatively understanding degradationin cells and in vivo. Here, we describe a case study where targeted proteomics
impacted a protein degrader project at AstraZeneca, by providing a key
orthogonal method to understand accurate DC50 and Dmax values.

11:35 Presentation to be Announced

9:05 Computational Structural Modeling of PROTACs and Molecular
Glues

Katherine Jones, Associate Science Director, Charles River LabsThis presentation will describe diverse hit identification strategies, such as
SAMDI-ASMS and DNA-encoded library screening, and their use to discoversmall molecule binders to novel targets. We will then describe how these hit
molecules can be validated and progressed through degrader optimisation
projects, including assay methodologies to measure molecular glue-like
properties.

Dima Kozakov, PhD, Associate Professor, Applied Mathematics & Statistics,
SUNY Stony Brook
The design of PROteolysis-TArgeting Chimeras (PROTACs) requires bringing
an E3 ligase into proximity with a target protein to modulate the concentrationof the latter through its ubiquitination and degradation. Here, we present
a combination of physics and machine learning methods for generating
high-accuracy structural models of E3 ligase-PROTAC-target protein ternarycomplexes. We will discuss the generalization of the approach for other TACs
and ligases, and principles of molecular glue discovery.

9:35 Networking Coffee Break
10:05 Parkin Ligase and PINK1 Signaling, Molecular Glue and its
Role in Neurodegenerative Diseases and Aging
Tauseef Butt, PhD, President & CEO, Progenra, Inc.
Parkinson’s disease (PD) and Alzheimer’s Disease (AD) share common
neurodegenerative traits, inability to correct protein misfolding or remove
aggregated proteins. Progenra has discovered a molecular glue that activates
parkin ligase and phospho-poly-ubiquitinate target proteins in cells and animalmodels. Blood-based levels of phospho-ubiquitin are important biomarkers for

16 | DiscoveryOnTarget.com

11:50 Presentation to be Announced
12:05 pm Transition to Lunch
12:10 LUNCHEON PRESENTATION: Identification andValidation of Novel Target Binders for Protein Degradersand Molecular Glues

12:40 Session BreakDEGRADATION STRATEGIES FOR CANCER
1:15 Chairperson’s Remarks
John Brognard, PhD, Senior Investigator, Laboratory of Cellular &Developmental Signaling, National Cancer Institute, National Institutes of
Health1:20 PIM1 Targeted Degradation Prevents the Emergence ofChemoresistance in Prostate Cancer
John Brognard, PhD, Senior Investigator, Laboratory of Cellular &Developmental Signaling, National Cancer Institute, National Institutes of
HealthCambridge Healthtech Institute’s 6th Annual

Degraders and Molecular Glues – Part 1
Design and Optimization of Novel Degraders and Glues | OCTOBER 1-2, 2024

PIM kinases have pro-tumorigenic roles and mediate several oncogenic
traits, including cell proliferation and survival. We found that inhibition of PIM
kinase activity stabilizes PIM protein levels and this promotes resistance to
PIM inhibitors. We designed PIM PROTACs to target PIM for degradation.
PIM PROTACs downmodulated PIM levels through the ubiquitin-proteasome
pathway. Degradation of PIM kinases was more potent than inhibition of
catalytic activity at inducing apoptosis in prostate cancer.

1:50 Degradation of Siglec 7/9 to Reshape the Tumor
Microenvironment for Cancer Immunotherapy
Peng Wu, PhD, Professor, Chemical Physiology, Scripps Research Institute
Many patients fail to respond to anti-CTLA-4 and anti-PD-1-based checkpoint
blockade, suggesting that orthogonal immune checkpoints exist. Myeloid
cell-associated Siglecs-7 and -9 have recently been identified as glycoimmune
checkpoints. However, there is currently no antibody that can target both
Siglecs. We have developed a degrader that induces efficient degradation ofboth Siglecs, which showed excellent tumor control in several murine solid
tumor models when used alone or combined with anti-CTLA-4.

2:20 Sponsored Presentation (Opportunity Available)
2:50 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Structural and Mechanistic
Characterization of Degraders and Glues

Ralph Mazitschek, PhD, Assistant Professor, Harvard Medical School;
Co-Director of the Chemical Biology Platform, Center for Systems Biology,
Massachusetts General Hospital
Hua Xu, PhD, Director, Mechanistic Biology & Profiling, AstraZeneca

IN-PERSON BREAKOUT: Tackling Transcription Factors andOther Difficult-to-Drug Targets

John Brognard, PhD, Senior Investigator, Laboratory of Cellular &Developmental Signaling, National Cancer Institute, National Institutes of
HealthWankyu Lee, PhD, Senior Research Scientist, AstraZeneca
Pharmaceuticals
Peng Wu, PhD, Professor, Chemical Physiology, Scripps Research Institute3:35 Grand Opening Refreshment Break in the Exhibit Hall with
Poster Viewing and Best of Show Voting Begins
4:35 FEATURED PRESENTATION: Targeting the PI3K
Pathway in Cancers

Anwesha Dey, PhD, Director & Distinguished Scientist,
Discovery Oncology, Genentech Inc.
PIK3CA is one of the most frequently mutated oncogenes;
the p110α protein it encodes plays a central role in tumor cellproliferation. Inavolisib is a potent and selective p110α inhibitor that
promotes the degradation of mutated p110α. The significance of
this unique mechanism to trigger specific degradation of mutant
p110α without significant change in wild-type p110α protein may result in
improved therapeutic index in PIK3CA-mutant tumors.

5:05 The Evolving Chemical Space of Bi-functional Degraders
Targeting the CNS
Wylie S. Palmer, PhD, Senior Director, Nurix Therapeutics, Inc.
Description:Bi-functional degraders occupy beyond-rule-of-five chemical
space where established rules for drug-likeness cannot easily be applied. In
contrast to approved CNS drugs, bi-functional degraders violate most metrics,
particularly molecular weight, yet we routinely observe brain penetrance inour programs. For example, NX-5948, a clinical stage orally bioavailable BTK
degrader shows CNS exposure and activity both preclinically and clinically.
This presentation will explore our evolving understanding of targeting the CNS
using degraders.

5:35 IKZF2 Degrader Discovery
Kevin D. Freeman-Cook, PhD, Vice President & Head, Medicinal &Computational Chemistry, Plexium Inc.
The zinc finger transcription factor Helios (IKZF2) is highly expressedin Tregs and plays an important role in helping tumors evade a normal
immune response. IKZF2 is a transcription factor that had been considered“undruggable.” Here we disclose the discovery and preclinical evaluation of a
selective molecular glue degrader of IKZF2 (PLX-4545) which reverses Treg
suppression and is currently being evaluated in a Phase 1 trial of healthy
volunteers.

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
7:05 Close of Day
WEDNESDAY, OCTOBER 2

7:30 am Registration Open and Morning Coffee

TARGETING TRANSCRIPTION
7:55 Chairperson’s Remarks
Danette Daniels, PhD, Vice President, Degrader Platform, Foghorn Therapeutics

8:00 FEATURED PRESENTATION: Attenuating
Oncogenic Transcription

Angela Koehler, PhD, Associate Professor, BiologicalEngineering, Massachusetts Institute of Technology
Outside of nuclear receptors, transcription factors havetraditionally been considered “undruggable” by small molecules due
to significant structural disorder and lack of defined binding pockets.
I will review successful targeting strategies, including discussion ofcompounds that modulate MYC-driven transcription via mechanisms
involving the MAX partner protein or the transcriptional kinase CDK9.
New directions for cancer target classes beyond transcription factors will
be discussed, including RNA-binding proteins and cytokines.

9:00 The Discovery and Characterization of Selective CREB-Binding
Protein (CBP) Degraders
Darshan Sappal, Director, Biology, Foghorn Therapeutics
Leveraging our expertise in targeted protein degradation at Foghorn
Therapeutics, we will describe our efforts at successfully identifying andcharacterizing potent, highly selective CBP heterobifunctional degraders withbiological activity in CBP-dependent cancer lines.

9:30 Targeted Protein Degradation (TPD): A New
Frontier in Drug Discovery
Alessandro Cinti, Principal Investigator Proposal, Axxam

DiscoveryOnTarget.com | 17

Cambridge Healthtech Institute’s 6th Annual

Degraders and Molecular Glues – Part 1
Design and Optimization of Novel Degraders and Glues | OCTOBER 1-2, 2024

Targeted Protein Degradation (TPD) offers a novel approach to modulate theintracellular levels of disease-causing proteins. Here, we will delve into thepractical aspects of TPD, focusing on the development and implementationof cell-based assays aimed at monitoring target protein levels, and will
discuss how complementary cell-based and cell-free assays support
the discrimination of unspecifically interfering compounds and detailed
characterization and further development of hit compounds.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

PLENARY KEYNOTE PROGRAM
10:50 Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Close of Degraders and Molecular Glues – Part 1
Conference

DiscoveryOnTarget.com | 18

Cambridge Healthtech Institute’s 6th Annual

Degraders and Molecular Glues – Part 2

New Targets, Ligases, Assays for Induced Proximity and Degradation
OCTOBER 2-3, 2024

WEDNESDAY, OCTOBER 2

PLENARY KEYNOTE PROGRAM
10:50 am Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Enjoy Lunch on Your Own

PROXIMITY-INDUCED THERAPEUTICS
1:45 Welcome Remarks
1:50 Chairperson’s Remarks
Adam Gilbert, PhD, Executive Director, Medicine Design, Pfizer Inc.

1:55 FEATURED PRESENTATION: Discovery of
Molecular Glues from Degraders to Stabilizers

Ryan Potts, PhD, Executive Director and Head, Induced
Proximity Platform, Amgen, Inc.
Induced proximity is a novel strategy for targeting thehighly intractable proteins that are involved in many human diseases.
By bringing together disease targets and biological effectors, such as
enzymes, ubiquitin ligases, or transcription factors, proximity-based
therapeutics can modulate the function, stability, or localization of thetarget proteins. My talk will cover new approaches for molecular glue
discovery for both degraders (beyond CRBN) and stabilizers of proteinprotein and protein-metabolite interactions.

19 | DiscoveryOnTarget.com

2:25 FEATURED PRESENTATION: Ubiquitin-Independent Protein
Degradation
Thomas Kodadek, PhD, Professor, Department of Chemistry, University of
Florida, Scripps Biomedical Research
Targeted protein degradation is usually achieved by bringing into
proximity a target protein and an E3 ubiquitin ligase. An alternative
strategy is to deliver the target directly to the proteasome and bypass
the requirement for poly-ubiquitylation. We present an engineered cellline that allows the strengths and weaknesses of ubiquitin-independentdegraders (UIDs) to be evaluated, as well as progress towards thediscovery of proteasome ligands for the development of UIDs.

2:55 Proximity Biosensor Assay for PROTAC Ternary
Complex Analysis
Ulrich Rant, Professor/Director, TU Dresden/Kurt-Schwabe-Institute for
Bioanalytical Systems
Ternary complexes present challenges in analyzing molecular interactions
due to their reliance on cooperativity and avidity, beyond binary affinities. We
introduce a proximity binding assay that simultaneously measures binary andternary interaction kinetics on a biosensor surface, using a Y-shaped DNA
scaffold and fluorescence methods. This assay is applied to CRBN, VHL, andvarious PROTACs, revealing insights into ternary complex stability and binding
kinetics.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 FIRESIDE CHAT: What Does the Future of Induced
Proximity-based Therapeutics Look Like?

Moderator: Adam Gilbert, PhD, Executive Director, Medicine Design, Pfizer
Inc.
Panelists:
Danette Daniels, PhD, Vice President, Degrader Platform, Foghorn
Therapeutics
Thomas Kodadek, PhD, Professor, Department of Chemistry, University of
Florida, Scripps Biomedical Research
Ryan Potts, PhD, Executive Director and Head, Induced Proximity
Platform, Amgen, Inc.

5:15 Dinner Short Course Registration**Premium Pricing or separate registration required. See Short Courses page fordetails.

5:15 Diversity Discussion (Sponsorship Opportunity Available)
IN-PERSON DISCUSSION: Fostering Diversity through Mentoring
Naytia Byrd, Manager, Human Resources, Ovid Therapeutics, Inc.
Saudat Fadeyi, PhD, MBA, Director, Business Development, Ovid
Therapeutics, Inc.
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics
Joel Omage, Research Scientist II, CVM Disease Area, Novartis Institutes
for BioMedical Research, Inc.
Andrew Zhang, PhD, Director, Chemical Biology, AstraZeneca
Topics for discussion will include, but certainly not be limited to:• How to increase awareness and address hidden barriers and biases inlife sciences• How to motivate early-career scientists to seek out mentors andresources• How to convince senior leadership to take time for coaching the next
generation of leaders and support DEI initiatives• How to create simple and impactful opportunities for mentors andmentees to connect and collaborate​​

Cambridge Healthtech Institute’s 6th Annual

Degraders and Molecular Glues – Part 2

New Targets, Ligases, Assays for Induced Proximity and Degradation
OCTOBER 2-3, 2024

6:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

8:30 Close of Day
THURSDAY, OCTOBER 3

7:30 am Registration Open and Morning Coffee

INSIGHTS FROM VENTURE CAPITALISTS
8:00 PANEL DISCUSSION: Trends in Drug Discovery

Moderator: Daniel A. Erlanson, PhD, Chief Innovation Officer, Innovation
and Discovery, Frontier Medicines Corporation
Panelists:
Jernej Godec, PhD, Principal, Atlas Venture
Jenna Hebert, PhD, Senior Associate, RA Capital Management
Jamie Kasuboski, PhD, Partner, Luma Group
Jasmina Marjanovic, PhD, Partner, Takeda Ventures
Swetha Murali, PhD, Vice President, OMX Ventures

EXPLORING NOVEL MOLECULAR GLUES
8:45 Chairperson’s Remarks
Yong Cang, PhD, Professor, ShanghaiTech University; Co-Founder & CSO,
Degron Therapeutics

8:50 Non-Degrading Molecular Glues—A Novel Platform for
Unlocking the Undruggable Genome
Rick Ewing, PhD, Vice President and Head of Chemistry, Rapafusyn
Pharmaceuticals
Non-degrading Type I molecular glues, FK506, Cyclosporin, and Rapamycin,
have delivered marketed therapies. The complex structures of thesemolecules have limited application to only a limited number of protein targets.
The presentation will describe construction of DEL and array libraries of
non-degrading molecular glues used for finding chemical starting points fora wide range of intracellular targets. Concepts of topological diversity, cellpermeability, and molecular glue characterization will be described.

9:20 NST-628 Is a Novel, Potent, Fully Brain-Penetrant MAPK
Pathway Molecular Glue That Inhibits RAS- and RAF-Driven Cancers

In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Novel Modalities, E3 Ligases andLigands for Induced Proximity

Tauseef Butt, PhD, President & CEO, Progenra, Inc.
Rick Ewing, PhD, Vice President and Head of Chemistry, Rapafusyn
Pharmaceuticals

IN-PERSON BREAKOUT: Discovery and Optimization of
Molecular Glues

Yong Cang, PhD, Professor, ShanghaiTech University; Co-Founder & CSO,
Degron Therapeutics
Susanta Samajdar, PhD, CSO, Aurigene Discovery Technologies Ltd.

11:05 Coffee Break in the Exhibit Hall with Poster Viewing and Bestof Show Awards Announced
11:45 Efficacy of a First-in-Class Polymerase Theta Degrader in
Preclinical Cancer Models
Susanta Samajdar, PhD, CSO, Aurigene Discovery Technologies Ltd.
Targeting PolΘ through degradation (glue or PROTAC) may provide theopportunity to ablate PolΘ entirely, which mimics the biological consequencesof a PolΘ genetic knockout. We shall present in vitro and in vivo data of our
first-in-class degrader of PolΘ for the first time.

12:15 pm A Molecular Glue Degrader of the WIZ Transcription Factor
for Fetal Hemoglobin Induction
Pamela Ting, PhD, Associate Director, Hematology, Novartis Institutes for
BioMedical Research
Sickle cell disease affects millions of people worldwide, disproportionately
in resource-limited regions. The development of a widely-accessible, oral
fetal hemoglobin (HbF) inducer has long been a goal. Here we leveraged achemical library of CRBN-biased molecular glues to explore HbF reactivation.
Phenotypic screening identified the transcription factor WIZ as a previously
unrecognized repressor of HbF. Chemical optimization generated potent WIZ
degraders, which were well-tolerated and induced HbF in preclinical models.

Klaus Hoeflich, PhD, CSO, Nested Therapeutics Inc.
Although targeting the RAS-MAPK has been the heartland of cancer research,high unmet clinical need remains. NST-628 is a molecular glue acting as
an induced stabilizer of key nodes in the RAS-MAPK pathway. With its
differentiated mechanism and superior drug-like properties, NST-628 has thepotential to provide transformative clinical benefit as both monotherapy andvertical combination anchor for RAS-MAPK-driven cancers.

1:20 Luncheon Presentation (Sponsorship Opportunity Available) or
Enjoy Lunch on Your Own

9:50 Degrading the RNA Binding Protein HuR to Treat BRAF Mutant
Cancer

1:50 Dessert Break in the Exhibit Hall with Last Chance for Poster
ViewingYong Cang, PhD, Professor, ShanghaiTech University; Co-Founder & CSO,
Degron Therapeutics
Human Antigen R (HuR), encoding by ELAVL1, binds and stabilizes mRNAs
encoding oncogenic drivers and proinflammatory cytokines. Using our
GlueXplorer discovery platform, we have identified novel CRBN-based
molecular glue degraders of HuR, a previously undruggable target, anddetermined BRAF mRNA as one of its major direct targets in cancer cells. A
preclinical candidate has been selected for development, and this first-in-classprogram is moving to clinical testing.

10:20 In-Person Breakouts

12:45 Sponsored Presentation (Opportunity Available)
1:15 Transition to Lunch

DEGRADING TRANSCRIPTION FACTORS
2:30 Chairperson’s Remarks
Kristy Stengel, PhD, Assistant Professor, Department of Cell Biology, Albert
Einstein College of Medicine

2:35 Targeted Transcription Factor Degradation Reveals Therapeutic
Vulnerabilities and Mechanisms of Regulation
Kristy Stengel, PhD, Assistant Professor, Department of Cell Biology, Albert
Einstein College of Medicine

DiscoveryOnTarget.com | 20

Cambridge Healthtech Institute’s 6th Annual

Degraders and Molecular Glues – Part 2

New Targets, Ligases, Assays for Induced Proximity and Degradation
OCTOBER 2-3, 2024

Transcription factors (TFs) are among the most frequently mutated and/ortranslocated genes in cancer, suggesting that a detailed understanding of theirmechanism-of-action could better define disease etiology and help identify
novel nodes for therapeutic intervention. Recently, our lab has employed novel
degron technologies to rapidly degrade TF proteins. This technology, whencombined with nascent transcript sequencing and multiomic readouts, allows
us to identify direct mechanisms of TF action.

3:05 Discovery of Highly Potent, Selective, and Efficacious STAT3PROTAC Degraders Capable of Achieving Long-Lasting Tumor
Regression
Haibin Zhou, PhD, Associate Research Scientist, Laboratory of Dr. Shaomeng
Wang, Department of Hematology & Oncology, University of Michigan
STAT3 is a transcription factor and a promising therapeutic target for cancer
and other human diseases. We have discovered a highly potent, selective,and efficacious STAT3 degrader UM-STAT3-1218. UM-STAT3-1218 is a highly
promising STAT3 degrader for the treatment of human cancers and otherhuman diseases in which STAT3 plays a key role.

3:35 Novel Heterobifunctional Modalities for Targeted Protein
Degradation and Stabilization
H. Ümit Kaniskan, PhD, Associate Professor, Laboratory of Dr. Jian Jin,
Department of Pharmacological Sciences, Icahn School of Medicine at Mt.
Sinai
The Jian Jin Laboratory at Icahn School of Medicine at Mount Sinai is aleader in discovering novel degraders targeting oncogenic proteins anddeveloping new technologies for advancing targeted protein degradation andstabilization. Our lab’s recent progress will be presented featuring our latest
studies such as Methyl-PROTAC, Z-PROTAC, and more.

4:05 Degradation of Nuclear Receptors for Oncology: AR Degrader
HP518 and ER Degrader HP568
Wu Du, PhD, Senior Vice President, Department of Medicinal Chemistry, Hinova
Pharmaceuticals, Inc.
Hinova discovered highly potent and orally available AR degrader HP518 andER-targeting degrader HP568. HP518 demonstrated an excellent preclinicalprofile and is currently in Phase I/II clinical trial. Thus far, HP518 has showeda satisfactory safety profile and encouraging efficacy signals in heavily
pretreated prostate cancer patients. HP568 showed oral PK and preclinicalefficacy superior to current leading AR degraders. Both compounds arepromising best-in-class AR and ER degraders.

4:35 Close of Conference

DiscoveryOnTarget.com | 21

Cambridge Healthtech Institute’s 8th Annual

Lead Generation Strategies
Small Molecule Drug Discovery Innovations | OCTOBER 1-2, 2024

TUESDAY, OCTOBER 1

7:00 am Registration Open and Morning Coffee

DNA-ENCODED LIBRARY INNOVATIONS
7:55 Welcome Remarks
8:00 Chairperson’s Remarks
Rachael Jetson, PhD, Senior Director, Lead Discovery, Valo Health

8:05 First-in-Class PiK3 Inhibitor from DEL Selection

10:35 New Leads against HIV Targets: Invention of the HIV-1
Maturation Inhibitor VH3739937 (VH-937)
Alicia Regueiro-Ren, PhD, Scientific Senior Director, Medicinal Chemistry,
Bristol Myers Squibb Co.
GSK-3532795/BMS-955176, an inhibitor of HIV-1 maturation was an effective
antiviral agent in HIV-1 infected substrates including those with the preexisting
polymorphisms that hadn’t responded to the first-generation maturation
inhibitor (MI) bevirimat. An optimization campaign identified GSK3640254 andVH3739937 (VH-937) as MIs with enhanced antiviral and safety profiles. Bothcompounds demonstrated efficacy in the clinic, GSK3640254 as a QD oral
agent and VH-937 as an agent with potential for infrequent dosing.

Ching-Hsuan Tsai, PhD, Director, Discovery Technologies, Relay Therapeutics,
Inc.
Treatments for PIK3CA-mutant cancers are limited by toxicities associatedwith the inhibition of WT PI3Ka. I will describe how Relay Therapeutics
integrates our Dynamo Platform with DEL screening to identify mutantselective chemical starting points. From these starting points came thedevelopment of RLY-2608, a first-in-class inhibitor demonstrating mutant
selectivity in patients.

11:05 Case-Studies of Delivering First-in-Class Targets with DEL

8:35 The Role of on-DNA Hit Confirmation in DNA-Encoded Library
Screening

11:35 Talk Title to be Announced

Karanbir Pahil, PhD, Investigator, Affinity Selections & Biophysics,
GlaxoSmithKline
DNA-encoded libraries enable us to identify thousands of hits from screensusing billions of molecules, producing a vast array of potential chemicalmatter that needs to be triaged efficiently. Here, we show how we leverage
the facility of resynthesizing screening hits on-DNA to enable biophysicalfollow-up. Ultimately, this enables us to make decisions on chemistry resource
investments, including synthesis of compounds that may not have been
obvious during data analysis.

Timothy L. Foley, PhD, Senior Principal Scientist & Lab Head, DNA Encoded
Library Selection & Pharmacology, Pfizer Global R&D Groton Labs
Identifying small molecule ligands to unprecedented targets is a significant
hurdle in drug discovery. DNA-encoded library (DEL) technology is an
important component of our Hit ID toolbox. Through a series of case-studies
I will discuss lessons learned in the use of DEL to discover hits for emerging
targets that represented first-in-class opportunities within our global portfolio.
Fangchao Liu, , HitGen Inc.

12:05 pm Transition to Lunch
12:10 LUNCHEON PRESENTATION: Recent Trends,
Limitations, and New Opportunities in Covalent Drug
Discovery

9:35 Networking Coffee BreakDaniel St-Cyr, Associate Principal Scientist, X-Chem, Inc.
As demonstrated by the approval of more than 30 covalent drugs, the growthin covalent drug discovery has changed the pharmaceutical landscape. We
can now target a wider variety of amino acid residues with an ever-increasing
diversity of warheads. From an analysis of recent covalent patents, the focus
on KRAS, EGFR, BTK, and FGFR with acrylamide warheads is evident. GSH
half-life to gauge intrinsic reactivity remains popular, but a clear consensus
on the exact boundary between desirable and excessive reactivity is missing.
There are also debates on whether traditional methods to describe covalent
inhibitor potency are valid, which time-independent constants are mostuseful, and whether reversible complex formation or reactivity rate determine
efficacy. This field is rapidly evolving with new warheads, new mechanistic
and kinetic understanding, and novel opportunities. This presentation will
focus on recent trends in the covalent patent literature, expanded DEL
covalent libraries that incorporate recently validated warheads, and improved
methods to assess nonspecific warhead reactivity.

PPI LEAD GENERATION CASE STUDIES

12:40 Session Break

9:05 Phenotypic DEL in Droplets for TPD and Beyond
Ken Yamada, PhD, Associate Director, Global Discovery Chemistry, Novartis
BioMedical ResearchThis talk will describe microfluidics-enabled cellular phenotypic DEL
workflow—MicDrop. We will introduce molecular glue degrader concept withan example and its potential implications, how we overcame the challenges
to perform cellular DEL screen in droplets, followed by results from a cellular
protein degradation screen with a validation library. Our results show how
this new paradigm of DEL screen can accelerate the field of molecular glue
discovery, and beyond.

10:05 FEATURED PRESENTATION: High-Dimensional
Biology and AI/ML to Accelerate Lead Identification
and Optimization

Samantha J. Allen, PhD, Scientific Director, High Dimensional
Biology & Cellular Pharmacology, Janssen R&D LLC
High-dimensional approaches and AI/ML hold great promise in drug
discovery from target identification to candidate selection. At Johnson& Johnson we’ve built capabilities to drive a data paradigm shift andaccelerate small molecule discovery through the large-scale generationand integration of unbiased high-dimensional data with AI/ML. In thispresentation I’ll describe our platform along with portfolio applications
from lead identification to lead optimization.

22 | DiscoveryOnTarget.com

BIOPHYSICAL TOOLS AND FRAGMENT-BASEDAPPROACHES FOR HIT-FINDING
1:15 Chairperson’s Remarks
Daniel A. Erlanson, PhD, Chief Innovation Officer, Innovation and Discovery,
Frontier Medicines Corporation

1:20 Beyond Isotopic Labeling: Measuring Small Molecule Affinities
to Proteins Using 1D-Diffusion Filtered NMR
Thomas E. Frederick, PhD, Senior Scientist II, Biophysics & Fragment
Screening, Abbvie

Cambridge Healthtech Institute’s 8th Annual

Lead Generation Strategies
Small Molecule Drug Discovery Innovations | OCTOBER 1-2, 2024

Protein-detect NMR is widely used in lead discovery campaigns for measuring
small molecule interactions with proteins and provides a robust measure of
weak affinities. This approach generally requires isotopic labeling. Here, I
will discuss an approach for measuring affinities of small molecule ligands
to unlabeled proteins that uses a 1D-diffusion filter and ECHOS analysis.
This enables protein-detect NMR as a method to characterize ligand-protein
interactions for most protein targets.

1:50 Fab-Induced Stabilization of an Ion Channel Enables BiosensorBased Mechanistic Characterization for Early Development of Small
Molecule Therapeutics
Soo Ro, PhD, Senior Scientist I, Biophysics, Genentech Inc.
SPR characterization of interactions between small molecule (SM)therapeutics and membrane proteins is extremely challenging, due to loss ofprotein activity on the sensing surface and signal interference from detergent
micelles. Here, we report SPR characterization of interactions between SMs
and an ion channel stabilized in complex with antigen-binding fragments
in conditions with low micelle interference, progressing SM therapeutic
development of an ion channel target.

2:20 Chemoproteomic Discovery of Covalent Binders to
Undruggable Targets in Living Cells
Nan Chen, CEO, ChomiX Biotech Co., Ltd.
In this presentation, I will describe our self-designed automated chemical
proteomic workstation. Utilizing a meticulously crafted cysteine-targeted
covalent library, we aim to leverage ChomiX’s automated platform for theidentification of specific binders to a series of undruggable targets, suchmembrane proteins and E3 ligases within living cells.

2:35 Sponsored Opportunity
2:50 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Affinity Selection-Mass Spectrometry(AS-MS) for de novo Hit Generation and DEL Hit Verification

Allen Annis, PhD, Independent Consultant, former SVP Research, Aileron
Therapeutics
Hans-Peter N. Biemann, PhD, Distinguished Scientist, Integrated Drug
Discovery, Sanofi• AS-MS and DEL as synergistic tools for hit generation and verification of
on- and off-DNA hit structures• Where does AS-MS fit in the HTS toolbox vs. DEL and other biophysical/
biochemical screening technologies?
• How do we access AS-MS for hit-finding and verification? Outsourcing
options vs. in-house platform development​

IN-PERSON BREAKOUT: Hit Validation Strategies

Mitchell H. Keylor, PhD, Associate Principal Scientist, Merck• Eliminating false positives• Data analysis formats• Binding methods: How important is it? Favorite biophysical tools?​

3:35 Grand Opening Refreshment Break in the Exhibit Hall with
Poster Viewing and Best of Show Voting Begins

4:35 FEATURED PRESENTATION: Covalent Fragments

Kate Carroll, PhD, Associate Professor, Chemistry, Florida Atlantic
University
Chemoproteomics reveals a vast expanse of ligandable cysteine sulfenic
acids in the human proteome highlighting the utility of small molecules in
the fragment-based, covalent-based ligand discovery pipeline.

5:05 Structure-Based Approach to Screen and Characterize RNATargeted Small Molecules
Yaqiang Wang, PhD, Principal Scientist, Chemical Sciences & Structural
Biology, Arrakis Therapeutics
RNA plays a ubiquitous role in every facet of the cell life cycle, and its
dysregulation frequently underlies various diseases. Arrakis’s mission is tosolve very broadly the problem of how to drug RNA with small molecules.
This presentation covers RNA structure identification, screening, and hit
characterization. We utilize an integrative structural biology approach todecipher RNA/ligand interactions and accelerate ligand optimization.

5:35 High-Throughput Crystallography and Structure-Based Design
for CDK7
Manjeet Mukherjee, PhD, Senior Research Associate, Astex Pharmaceuticals,Ltd.
I will highlight how we enabled a structural system for cancer target CDK7
to perform structure-based drug design. I will show examples of liganded
complexes with clinical stage compounds in both covalent and non-covalentmodalities and discuss how that impacted our drug lead design.

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
7:05 Close of Day
WEDNESDAY, OCTOBER 2

7:30 am Registration Open and Morning Coffee

SMALL MOLECULE REGULATORS OF MEMBRANE
PROTEINS
7:55 Chairperson’s Remarks
Samantha J. Allen, PhD, Scientific Director, High Dimensional Biology & Cellular
Pharmacology, Janssen R&D LLC

8:00 Discovery and Characterization of JNT-517, an Inhibitor of
SLC6A19 for the Treatment of Phenylketonuria
Dean G. Brown, PhD, Vice President & Head, Chemistry, Jnana Therapeutics
The discovery efforts using our RAPID (Reactive Affinity Probe Interaction
Discovery) chemoproteomics platform will be described that led to small
molecules that inhibited transporter SLC6A19 and demonstrated in vivo
activity in the Pahenu2 model. This work led to the identification of JNT-517, a
potential first-in-class clinical candidate for the treatment of phenylketonuria
which has demonstrated positive POC in a Ph1b clinical trial.

8:30 Optimization of Allosteric Regulators of the NaV1.7 Sodium
Channel for Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Se In Son, PhD, Research Scientist, Chemistry, NIH NCATS
NCATS and Regulonix developed NaV1.7 channel regulators by targeting
CRMP2 sumoylation, which is an allosteric regulator of the channel. Regulonix
discovered that surface expression of the channels can be decreased due toloss of CRMP2 sumoylation. Through virtual screening and hit search, leadcompound AZ194 was discovered. The NCATS team expanded the libraryof inhibitors from AZ194 to more than 450 analogs, with novel structures,
improved potency, and ADME properties.

DiscoveryOnTarget.com | 23

Cambridge Healthtech Institute’s 8th Annual

Lead Generation Strategies
Small Molecule Drug Discovery Innovations | OCTOBER 1-2, 2024

9:00 TREM2 Molecular Glues to Treat Neurodegenerative Diseases
Bhaumik A. Pandya, PhD, Director, Chemistry Vigil Neuroscience
Triggering receptor expressed in myeloid cells 2 (TREM2) is a lipid-sensing
receptor that promotes the growth, migration, and anti-inflammatory effectsof microglia that are upregulated within pathological microenvironments.
Loss-of-function TREM2 variants impose genetic risk for Alzheimer’s disease(AD). Herein we highlight the activity and profile of Vigil’s first-in-class small
molecule TREM2 agonists for treatment of neurodegenerative diseases.

9:30 Using High-Content Imaging to Drive Small
Molecule Protein Degraders from Hit to Lead
Clark Driscoll, Sr. Research Scientist , Curia
Using High-Content Imaging to Drive Small Molecule Protein Degraders from
Hit to Lead: While PROTACs and targeted degrader programs have proven tobe successful, small molecule degrader screening remains a viable approach
when coupled with a well-developed screening platform. In this case study wedescribe the development of a high content screening and lead optimization
platform for small molecule degraders. By front-loading data across multiple
targets, this approach accelerated the discovery pipeline and enabledclassification of compounds with unique phenotypic profiles.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

PLENARY KEYNOTE PROGRAM
10:50 Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Close of Lead Generation Strategies Conference

DiscoveryOnTarget.com | 24

Cambridge Healthtech Institute’s 21st Annual

Target Identification Strategies
Effective Use of Chemoproteomics, Functional Genomics, and AI/ML for
Target Discovery | OCTOBER 2-3, 2024

WEDNESDAY, OCTOBER 2

PLENARY KEYNOTE PROGRAM
10:50 am Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Enjoy Lunch on Your Own

PROTEOMICS-DRIVEN TARGET DECONVOLUTION
1:45 Welcome Remarks
1:50 Chairperson’s Remarks
Christopher am Ende, PhD, Associate Research Fellow, Internal Medicine
Medicinal Chemistry, Pfizer Inc.

1:55 Developing and Applying a Novel Chemoproteomics Platformfor Transcription Factor Drug Discovery
Sherry Niessen, PhD, Vice President, Proteomics, Belharra Therapeutics
applying a novel chemistry enabled non-covalent probe library and quantitative
mass spectrometry to identify chemical probes that selectively bind any
pocket, on any protein, in live cells. The platform is identifying chemicalprobes that selectively engage diverse protein classes. Most proteins
identified by our probe library do not have a reported ligand in drug bankdemonstrating the ability of the platform to identify novel pockets and starting
points for probes.

25 | DiscoveryOnTarget.com

2:25 FEATURED PRESENTATION: Combining Sample
Multiplexing and Targeted Proteomics to Screen
Electrophilic Fragment Libraries

Steve Gygi, PhD, Professor, Department of Cell Biology,
Harvard Medical School
Covalent modification of cysteines by libraries of fragment electrophiles
can be assessed proteome-wide using chemoproteomics techniques.
In this talk, I will present the CysDig strategy which exploits the directtargeting of a few hundred cysteines for quantification. Importantly,
this approach is flexible such that biotin enrichment is optional and theprotein’s expression levels can also be assessed. An example targetedlibrary screen for E3 ligase binders identified a Huwe1 inhibitor.

2:55 Sponsored Presentation (Opportunity Available)
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 Advancing Chemical Biology through Innovative Chemistry
Christopher am Ende, PhD, Associate Research Fellow, Internal Medicine
Medicinal Chemistry, Pfizer Inc.
This presentation explores new reactive moieties for protein labeling througha series of vignettes. It focuses on the mechanistic analysis and proteomewide labeling capabilities of cyclobutyl diazirine probes and the large-scaleproteomic analysis of diazirine photoaffinity probes—as well as the broad
utility of tetrazines as bioorthogonal handles, in addition to protein labelingapplications.

4:45 Systematic Identification of Condensate Targets andDevelopment of Condensate-Modifying Drugs (c-mods) across
Therapeutic Areas
Ann Boija, PhD, Vice President, Head of Cancer Biology, Dewpoint Therapeutics
Condensates regulate cellular processes by concentrating and organizing
biomolecules within communities with distinct microenvironments.
Condensate aberrations serve as central nodes of dysfunction in many
diseases. Viewing condensates as drug targets opens untapped opportunities
to influence high value, “undruggable” drug targets. Our AI-powered
discovery platform supports identification of condensate-drivers of diseases,
development of disease-faithful models, and discovery & developmentof c-mods, fueling programs across multiple therapeutic areas, including
oncology and neurodegeneration.

5:15 Dinner Short Course Registration**Premium Pricing or separate registration required. See Short Courses page fordetails.

5:15 Diversity Discussion (Sponsorship Opportunity Available)
IN-PERSON DISCUSSION: Fostering Diversity through Mentoring
Naytia Byrd, Manager, Human Resources, Ovid Therapeutics, Inc.
Saudat Fadeyi, PhD, MBA, Director, Business Development, Ovid
Therapeutics, Inc.
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics
Joel Omage, Research Scientist II, CVM Disease Area, Novartis Institutes
for BioMedical Research, Inc.
Andrew Zhang, PhD, Director, Chemical Biology, AstraZeneca
Topics for discussion will include, but certainly not be limited to:• How to increase awareness and address hidden barriers and biases inlife sciences• How to motivate early-career scientists to seek out mentors andresources• How to convince senior leadership to take time for coaching the next
generation of leaders and support DEI initiatives

Cambridge Healthtech Institute’s 21st Annual

Target Identification Strategies
Effective Use of Chemoproteomics, Functional Genomics, and AI/ML for
Target Discovery | OCTOBER 2-3, 2024

• How to create simple and impactful opportunities for mentors andmentees to connect and collaborate​​

6:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

8:30 Close of Day
THURSDAY, OCTOBER 3

7:30 am Registration Open and Morning Coffee

INSIGHTS FROM VENTURE CAPITALISTS
8:00 PANEL DISCUSSION: Trends in Drug Discovery

Moderator: Daniel A. Erlanson, PhD, Chief Innovation Officer, Innovation
and Discovery, Frontier Medicines Corporation
Panelists:
Jernej Godec, PhD, Principal, Atlas Venture
Jenna Hebert, PhD, Senior Associate, RA Capital Management
Jamie Kasuboski, PhD, Partner, Luma Group
Jasmina Marjanovic, PhD, Partner, Takeda Ventures
Swetha Murali, PhD, Vice President, OMX Ventures

FUNCTIONAL SCREENING FOR TARGET ID
8:45 Chairperson’s Remarks
Sujatha Gopalakrishnan, Director, Research Fellow, Head of HTS & Molecular
Characterization, AbbVie

8:50 Uncovering Potential Anti-Coronavirus Agents: Phenotypic
Screening and Target Identification of Compounds Targeting
Nucleocapsid N Protein
Sujatha Gopalakrishnan, Director, Research Fellow, Head of HTS & Molecular
Characterization, AbbVie
The urgent need for effective therapeutics against coronaviruses has
prompted the development of innovative drug discovery approaches. In thisstudy, we established a robust high-content screening platform to identify
small molecules capable of modulating the condensation of the SARS-CoV-2
Nucleocapsid (N) protein. Our promising results demonstrate that perturbing
viral condensate dynamics can generate effective antiviral drugs for multiple
viral species, including SARS-CoV-2.

9:20 QUANTROseq: A Transcriptomic Platform Matching Drugs to
Their Targets
Arianna Sabo, PhD, Head, Research & Discovery, Quantro Therapeutics GmbHQUANTRO developed QUANTROseq, an innovative platform able to map small
molecules to their targets by matching transcriptional fingerprints producedby drug candidates with the ones obtained by controlled acute degradation of
the target-of-interest. Using this technology at-scale, QUANTRO demonstrated
that time-resolved transcriptional profiling reveals drugs´ mode-of-action with
unprecedent precision and sensitivity and enables discovery of NCE against
previously undruggable targets.

9:50 Toward a Universal Toolbox of Valuable Building Blocks for
Chemical Biology Probe Synthesis
David Lapinsky, PhD, Associate Professor, Medicinal Chemistry, Duquesne
University School of Pharmacy and Graduate School of Pharmaceutical
Sciences

Clickable covalent compounds are some of the most valuable smallmolecules one could pursue, given their numerous applications. However,merging a ligand/protein-recognition element, a protein-reactive functionalgroup, and a bioorthogonal chemistry reporter group into a single chemicalprobe is non-trivial. This talk will highlight some of our work toward a universal
toolbox of valuable building blocks researchers can use to synthesize
clickable covalent probes for chemical biology-mediated drug discovery anddevelopment.

10:20 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Leveraging Covalent Chemistries,
Phenotypic Screening, Chemoproteomics Tools
Alexander Federation, PhD, Co-Founder & CEO, Talus Bioscience
Denise Field, PhD, Senior Principal Scientist, Chemical Biology andProteomics, Pfizer
Andrew Zhang, PhD, Director, Chemical Biology, AstraZeneca

11:05 Coffee Break in the Exhibit Hall with Poster Viewing and Bestof Show Awards Announced
11:45 Utilizing CRISPR-Suppressor Scanning to Functionally Map
Chromatin Complexes
Hui Si Kwok, PhD, Postdoctoral Fellow, Laboratory of Dr. Brian Liau, Departmentof Chemistry and Chemical Biology, Harvard University
Genes encoding chromatin proteins are among the top mutated cancer genes.
Interpreting the functional significance for every cancer mutation remains amajor obstacle for advancing cancer research. Using Polycomb repressive
complex 2 (PRC2) as a case study, I will showcase the utility of pooledtiling base-editing screens to define regulatory regions and understand thefunctional significance of cancer-associated mutations in their endogenous
context.

12:00 pm Systems-Wide Approaches for Mapping Substrates to E3
LigasesElijah Mena, PhD, Post-Doctoral Researcher, Laboratory of Dr. Stephen Elledge,
Department of Genetics, Harvard University Medical School
The complexity of the ubiquitin-proteasome system makes it challenging
to systematically pair proteasomal substrates to their cognate E3 ubiquitin
ligases. We have developed new technologies that are able to identify
ubiquitin-proteasome targets on a genome-wide scale and can pair thesesubstrates to E3s using multiplex CRISPR screening. Additionally, saturating
mutagenesis and computational approaches allow us to define the molecularbasis for many degradative pathways at scale.

12:15 Application of High-Density CRISPR Screens for Mutational
Scanning of Endogenous Elements
Ganna Reint, PhD, Postdoctoral Fellow, Broad Institute of Harvard and MIT
Assessment of the functional effects of DNA sequence variation is crucial
for an understanding of the genetic basis of human disease. We applied thenewest versions of base editors, coupled with the PAM-flexible Cas9, for
high-throughput interrogation of genetic variation at endogenous loci. High-DiscoveryOnTarget.com | 26

Cambridge Healthtech Institute’s 21st Annual

Target Identification Strategies
Effective Use of Chemoproteomics, Functional Genomics, and AI/ML for
Target Discovery | OCTOBER 2-3, 2024

coverage tiling enabled mapping of the functional regions in the proteins anddiscovering potential gain-of-function mutations across a panel of genes withstrong cancer dependencies.

12:30 Continuous Evolution of Compact Protein Degradation Tags
Regulated by Selective Molecular Glues
Stephan John DeCarlo, PhD Student, Laboratory of David Liu, Harvard
University
Shourya Roy Burman, PhD, Scientist, Cancer Biology, Dana-Farber Cancer
Institute
Conditional degron tags are >100 amino acids long or are triggered bycompounds with off-target effects, thwarting their use as specific modulatorsof endogenous protein levels. We evolved a 36-amino acid degron, SD40,
that binds cereblon in complex with an otherwise inert compound, PT-179.
Endogenous proteins tagged in-frame with SD40 using prime editing are
degraded by PT-179. Cryo-EM structures of SD40 in complex with ligandbound cereblon reveal molecular basis of SD40’s activity.

Interaction-based screening and design are promising novel strategies for
hit finding and lead optimization. The key information unit in the interaction
realm is a thin interface between the interacting ligand and protein. When fed
to deep neural networks, interaction signatures may infer SAR for unliganded
proteins by exploiting structural data across ligands and proteins. We give an
overview of the approach and describe its successful applications to several
challenging targets.

4:05 Assessment of Target Druggability Enabled by Machine
Learning

12:45 Sponsored Presentation (Opportunity Available)

Diane M. Joseph-McCarthy, PhD, Professor of the Practice, Biomedical
Engineering, Boston University
Identification of hot spots on the surface of macromolecules is key toevaluating the druggability of novel targets and the likelihood of finding new
chemical entities. Computational hot-spot mapping was performed across a
set of drug targets, and a machine learning approach was employed to selectthe top druggable sites. Within this context, the utility of AI-generated protein
models obtained using AlphaFold, including ensembles of structural models,
was assessed.

1:15 Transition to Lunch

4:35 Close of Conference

1:20 Luncheon Presentation (Sponsorship Opportunity Available) or
Enjoy Lunch on Your Own
1:50 Dessert Break in the Exhibit Hall with Last Chance for Poster
Viewing

AI-DRIVEN TARGET DISCOVERY
2:30 Chairperson’s Remarks
Harpreet Saini, PhD, Senior Director, Informatics, Astex Pharmaceuticals Ltd.

2:35 Integrative Computational Genetics Approach for Target
Discovery of ALS
Harpreet Saini, PhD, Senior Director, Informatics, Astex Pharmaceuticals Ltd.
We have developed a computational, genetics-based approach which
integrates functional data from GWAS, ontologies, and biological networks
to predict potential drug targets with evidence for disease association.
We obtained a list of target genes associated with ALS and prioritized
potential target genes by integrating structural information and cell-typetranscriptomics data.

3:05 FEATURED PRESENTATION: Target Discovery
Using AI—The Story behind Insilico Medicine’s
Discovery and Validation of MYT1 as a Target
Implicated in Breast Cancer

Petrina Kamya, PhD, Global Head of AI Platforms, Vice President Insilico
Medicine; President, Insilico Medicine Canada, Insilico
Using PandaOmics, we identified MYT1 as a promising new therapeutictarget for breast and gynecological cancer. PandaOmics is Insilico
Medicine’s AI-driven target discovery platform that leverages multi-modal
data to discover targets implicated in a disease. To further validate theselection of MYT1, we leveraged Chemistry42 to design and optimize alead compound that exhibits remarkable selectivity over WEE1 and has
promising in vivo antitumor efficacy.

3:35 Interaction-Based Hit Discovery Platform to Orphan Targets
Dmitri Kireev, PhD, Professor, Department of Chemistry, University of Missouri

DiscoveryOnTarget.com | 27

Cambridge Healthtech Institute’s 6th Annual

Small Molecules for Cancer Targets
Discovering Targeted, Oral-Based Oncology Therapeutics | OCTOBER 1-2, 2024

TUESDAY, OCTOBER 1

7:00 am Registration Open and Morning Coffee

COVALENT OR DEGRADER APPROACHES FOR RAS OR
WRN
7:55 Welcome Remarks
8:00 Chairperson’s Remarks
Mellissa Nixon, PhD, Senior Scientist, Merck Research Labs

8:05 Discovery of FMC-376 a Potent Dual Inhibitor of ‘ON’ and ‘OFF’
States of KRASG12C Broadly Active in PDX Models of Resistance
Snahel Patel, Vice President, Head, Medicinal & Platform Chemistry, Frontier
Medicines Corp.
Once viewed undruggable, frequently mutated oncogene KRAS has led to therecent approval of two KRASG12C small molecule covalent inhibitors targeting
the inactive GDP-bound (OFF) state. Patient benefit has fallen short withthese first-generation inhibitors due to innate or acquired resistance driven by
upregulation of the activated GTP-bound (ON) state of KRASG12C. We present
the discovery of potent dual inhibitor FMC-376 targeting both active andinactive forms of KRASG12C.

8:35 Tyrosine-Targeted Covalent Fragments for KRAS
Samy O. Meroueh, PhD, Professor, Biochemistry, Member of Cancer Center
Drug Discovery Program, University of Illinois Urbana-Champaign
I present my Ras GTPases (mainly Ral and KRAS) work where I usedfragment-screening to develop covalent inhibitors that react with tyrosines.
A tyrosine-based covalent approach expands the number of KRAS-origin
cancers that can be targeted because only 10% of KRAS genes have the
G12C mutation. I also discuss our progress with covalent inhibition of
Ral GPTase using tyrosine and will present a unique KRAS structure that I
recently published.

9:05 FEATURED PRESENTATION: Identification of
VVD-214/RO7589831, a Clinical-Stage, Covalent
Allosteric Inhibitor of WRN Helicase for theTreatment of MSI-High Cancers

Shota Kikuchi, PhD, Director, Chemistry, Vividion Therapeutics
WRN helicase is a promising target for treating cancers withmicrosatellite instability (MSI), due to its essential role in resolving
deleterious non-canonical DNA structures that accumulate in cells withfaulty mismatch repair mechanisms. Here we describe the medicinal
chemistry optimization of potency, ADME, and PK properties ofchemoproteomic screening hits, which resulted in identification of VVD214/RO7589831 (Vividion/Roche), a clinical-stage, covalent allostericinhibitor of WRN.

9:35 Networking Coffee BreakPROTEIN-STABILIZING STRATEGIES FOR CANCER
10:05 Rational Discovery of a Small Molecule Intramolecular Glue
Inhibitor of CBL-B that Enhances T-cell Function
Stefan Gajewski, PhD, Structural Biologist, Early Drug Discovery, Nurix
Therapeutics Inc
Casitas B lymphoma-b (CBL-B) is a RING-type E3 ubiquitin ligase that plays
an important role in regulating T cell function. Loss of CBL-B is associatedwith enhanced T and NK cell activity which makes it an interesting target

28 | DiscoveryOnTarget.com

for immuno-oncology drug development. We present a rational approach todiscover and optimize small molecule inhibitors for CBL-B that elicit a potent
T cell activation and antitumor activity.

10:35 Inhibiting CBL-B: An E3 Ligase Immuno-Oncology Target
Michael Lambrecht, PhD, Principal Scientist, Drug Discovery, Genentech
Knockout of the ubiquitin ligase cbl-b causes tumor rejection in murine
models and represents a promising target for cancer immunotherapy. We
screened a DNA-encoded library and discovered a xanthene-containing leadmolecule that bound to and inhibited cbl-b. An x-ray co-crystal structure
showed this lead molecule bound to the SH2 domain of cbl-b. Here we
describe these studies and a medicinal chemistry campaign that provided an
inhibitor with measurable cell activity.

11:05 Accelerating Inhibitor Discovery for Deubiquitinating
Enzymes
Wai Cheung Adrian Chan, PhD, Principal Scientist, Enabling Sciences, Odyssey
Therapeutics
Deubiquitinating enzymes (DUBs) are a class of ~100 cysteine proteases,of interest as emerging drug targets and for application in targeted protein
stabilization. Pairing a bespoke library with activity-based protein profilingas a high-density primary screen, we identify and validate a multitude ofpromising chemical starting points and a direct path to tool compounds thatcan be used to decipher DUB function, substrates, and signaling pathways.

11:35 Exploring the Power of Structural Biology on
Degrader Discovery
JIAQUAN WU, General Manager, Biortus
The emerging of protein degradation as a novel therapeutic modality has
attracted interest in broad drug discovery community. Unlike conventional
small molecular drug discovery, where SBDD has been widely adopted
for rational design of hit and lead molecules, the application of structural
biology to degrader discovery is only limited to the elucidation of the binding
mode of selected lead PROTAC or molecular glue molecules so far. Thisis largely due to two reasons: one being the lack of robust protocols toassemble stable degradation complexes, and the other being the less thandesired resolution of the complex structures solved by ether crystallography
or cryoEM. At Biortus, we strive to help the community to evolve degrader
discovery from experience-based design to SBDD by exploring our expertisein both protein chemistry and structural biology. We have now establishedrobust methodologies for PROTAC and molecular glue complex structure
determination using both crystallography and cryoEM, and are working
towards solutions to improve resolution for SBDD.

12:05 pm Transition to Lunch
12:10 LUNCHEON PRESENTATION: Biortus’s Protein
Focused Discovery Services: Protein Production, Assayand Screening, Crystallography, and CryoEM
Larry Jin, COO, Biortus
Biortus is a global leading service provider of target protein and structural
biology. Biortus implements AI-powered construct design for protein
expression in E. coli, insect cells, mammalian cells, yeast, CFS, and silkworm
systems. Accumulatively, Biortus has over 50,000 plasmids in stock, fromwhich over 3,000 unique target proteins have been expressed and purified,with over 300 being membrane proteins. Biortus’s hit finding capabilities
cover biochemical, biophysical, and cellular assay and screening, with several
internal fragment libraries for easy access and flexible screening schedule.
Biortus’s crystallography has delivered more than 7,000 xtal structures forover 600 unique targets, some of them being first-to-the-world structures.
Biortus’s cryoEM platform is the largest service facility so far, with 8 units ofThermoFisher electron microscopes and over 60 structural biologists working

Cambridge Healthtech Institute’s 6th Annual

Small Molecules for Cancer Targets
Discovering Targeted, Oral-Based Oncology Therapeutics | OCTOBER 1-2, 2024

exclusively on SPA, MicroED, and LNP/AAV characterization.
Biortus offers catalog proteins via VWR, Cayman, FisherSci, and several otherpartners. Biortus is a regular contributor to the PDB and EMDD database.

12:40 Session BreakDEGRADERS & CANCER
1:15 Chairperson’s Remarks
Philip N. Collier, PhD, Director, Medicinal Chemistry, Kymera Therapeutics

1:20 Abbapolin PLK1 Degraders in Prostate Cancer
Campbell McInnes, PhD, Professor, Drug Discovery & Biomedical Sciences,
University of South Carolina
Inhibition of PLK1 may be key to overcoming resistance to androgen blocking
treatments that result in Castration Resistant Prostate Cancer (CRPC)
providing new therapeutic options. Using the REPLACE strategy, we foundcompounds that bind tightly to PLK1 and induce its degradation. Through our
hit to lead conversion studies we identified an abbapolin with potent on target
cellular engagement of PLK1, good oral pharmacokinetics and antitumor
efficacy in prostate xenografts.

PIK3CA is one of the most frequently mutated oncogenes;
the p110α protein it encodes plays a central role in tumor cellproliferation. Inavolisib is a potent and selective p110α inhibitor that
promotes the degradation of mutated p110α. The significance of
this unique mechanism to trigger specific degradation of mutant
p110α without significant change in wild-type p110α protein may result in
improved therapeutic index in PIK3CA-mutant tumors.

5:05 The Evolving Chemical Space of Bi-functional Degraders
Targeting the CNS
Wylie S. Palmer, PhD, Senior Director, Nurix Therapeutics, Inc.
Description:Bi-functional degraders occupy beyond-rule-of-five chemical
space where established rules for drug-likeness cannot easily be applied. In
contrast to approved CNS drugs, bi-functional degraders violate most metrics,
particularly molecular weight, yet we routinely observe brain penetrance inour programs. For example, NX-5948, a clinical stage orally bioavailable BTK
degrader shows CNS exposure and activity both preclinically and clinically.
This presentation will explore our evolving understanding of targeting the CNS
using degraders.

5:35 IKZF2 Degrader Discovery

Murali Ramachandra, PhD, CEO, Aurigene Discovery Technologies, Ltd.
Despite recent advances in KRAS inhibitors for cancer therapy, a majority of
KRAS alterations remain unaddressed. The rapid emergence of resistance
where inhibitors are available underscores the need for novel approaches. We
will discuss our focus on targeted protein degradation to eliminate mutant
KRAS as a promising avenue for superior and durable efficacy.

Kevin D. Freeman-Cook, PhD, Vice President & Head, Medicinal &Computational Chemistry, Plexium Inc.
The zinc finger transcription factor Helios (IKZF2) is highly expressedin Tregs and plays an important role in helping tumors evade a normal
immune response. IKZF2 is a transcription factor that had been considered“undruggable.” Here we disclose the discovery and preclinical evaluation of a
selective molecular glue degrader of IKZF2 (PLX-4545) which reverses Treg
suppression and is currently being evaluated in a Phase 1 trial of healthy
volunteers.

2:20 Presentation to be Announced

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing

2:35 Presentation to be Announced

7:05 Close of Day

1:50 Discovery and Development of pan-KRAS Degraders for Cancer
Therapy

3:05 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Covalent Approaches for Drug
Discovery

Paul E. Gormisky, PhD, Senior Director, Enabling Sciences Chemistry,Odyssey Therapeutics• Strategies to prioritize targets for covalent drug discovery• Assessing if a covalent ligand or fragment for a novel target can be
progressed to a drug (e.g., sufficient pocket, supportive biology)• Role of covalency in other new modalities (degraders, macrocycles)​

3:35 Grand Opening Refreshment Break in the Exhibit Hall with
Poster Viewing and Best of Show Voting Begins
4:35 FEATURED PRESENTATION: Targeting the PI3K
Pathway in Cancers
Anwesha Dey, PhD, Director & Distinguished Scientist,
Discovery Oncology, Genentech Inc.

WEDNESDAY, OCTOBER 2

7:30 am Registration Open and Morning Coffee

SMALL MOLECULE IMMUNO-ONCOLOGY TARGETS
7:55 Chairperson’s Remarks
Jenny Chengyi Shu, PhD, Senior Director, Biology Immunology, Life Mine
Therapeutics

8:00 Structure-Based Design of DHODH Inhibitors for the Treatmentof Acute Myelogenous Leukemia
Justin Cisar, PhD, Principal Scientist, Medicinal Chemistry, Janssen
Pharmaceuticals Inc.

8:30 Identification of a Novel Linker Enabling Bioconjugation of a
Cyclic Dinucleotide for the STING Antibody-Drug Conjugate TAK-500
Hong Myung Lee, PhD, Senior Scientist, Medicinal Chemistry, Takeda
Pharmaceuticals Inc.
The chemistry strategy was established to enable targeted delivery of acyclic dinucleotide STING agonist TAK-676 to CCR2+ myeloid cells throughan antibody-drug conjugate approach. A self-immolative spacer between
the adenine of TAK-676 and the cleavable dipeptide linker rendered a linker
payload with enhanced plasma stability. Stochastic cysteine conjugation of
the linkers provided immune cell-stimulating ADC TAK-500. In mouse models,
mTAK-500 showed antitumor activity driven by immune cell activation.

DiscoveryOnTarget.com | 29

Cambridge Healthtech Institute’s 6th Annual

Small Molecules for Cancer Targets
Discovering Targeted, Oral-Based Oncology Therapeutics | OCTOBER 1-2, 2024

9:00 GPCRs of the Tumor Microenvironment as Novel ImmunoOncology Drug Targets
Stephan Schann, PhD, CSO, Domain Therapeutics SA
Immunotherapy has revolutionized cancer treatment, including metastatic
disease cures. However, many patients do not benefit from immunotherapy
due to multiple resistance mechanisms. At Domain, our innovative approach
focuses on precision. Our unique pipeline of GPCR targeting drug candidates
targets immunosuppressive mechanisms, unlocking new therapeutic
possibilities in cancer. In this presentation, we’ll explore the identificationof novel immunosuppressive GPCRs and small molecule drug discovery,emphasizing Domain’s precision research approach.

9:30 Quantification of Small Molecule andPhosphopeptide Binding Affinity Selectivity AcrossHuman SH2 Domains Assays
Jean Bernatchez, Sr Scientist & R&D Grp Leader, Eurofins Discovery
SH2 domains are an emerging target class for the development of small
molecules which disrupt protein-protein interactions, as well as for thedevelopment of targeted protein degraders. We present screening validation
data against a panel of 95 wild type and 7 mutant SH2 domain assays for acollection of reported small molecules and peptides which bind to this proteinprotein interaction module.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

PLENARY KEYNOTE PROGRAM
10:50 Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Close of Small Molecules for Cancer Targets Conference

DiscoveryOnTarget.com | 30

Cambridge Healthtech Institute’s 19th Annual

GPCR-Based Drug Discovery

Targeting G Protein-Coupled Receptors for New Therapeutic Options
OCTOBER 2-3, 2024

WEDNESDAY, OCTOBER 2

PLENARY KEYNOTE PROGRAM
10:50 am Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

Despite the increasing availability of high-resolution GPCR structures, finding
allosteric modulators remains challenging due to the dynamic nature of
GPCRs in native membranes. I present a novel strategy to site-specificallycovalently tether drug fragments adjacent to allosteric sites in engineered
GPCRs harboring noncanonical reactive amino acids. This approach enhances
compound potency, enabling fragment-based drug screening and thediscovery of new functional allosteric binding sites using live-cell assays.

2:55 Accelerate the Development of Therapeutics for
Obesity and Diabetes with Functional Cell-based Assays
Venkatesh Chari, Scientific Market Development Manager, Eurofins DiscoverX
GPCR-based peptide therapeutics have shown promise in treating obesityand diabetes. The development of innovator drugs, biosimilars and small
molecules for these globally prevalent conditions require demonstration of
accurate mechanism of action and pharmacology crucial to characterize
their true therapeutic potential. Here, we present fit-for-purpose assays forevaluating therapeutics targeting GLP-1, GIP, glucagon, TSH, PYY, amylin,
GPR10, and GPR75 receptors to accelerate global programs for screening,
characterization, and potency testing.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 FEATURED PRESENTATION: SPR-Microscopy for Detecting
GPCR Target Engagement
Kris A. Borzilleri, Principal Scientist, Structural Biology & Molecular
Sciences, Pfizer Global R&D, Groton Labs
Measuring direct binding and kinetics to membrane proteins has long
been a challenge due to poor behavior of these targets when purified outof their native environments. Surface Plasmon Resonance Microscopy(SPRm), which combines optical microscopy with label-free SPR, allows
for detection of binding in the whole cell environment. Using SPRm,
we measured binding affinities on several targets that are in excellent
agreement with radioligand binding and functional IC50 assays.

4:45 DNA-Encoded Library Approaches for GPCR-Ligand Discovery

NMR, FRAGMENTS & OTHER NEW TOOLS FOR GPCR
DRUG DISCOVERY

Casey J. Krusemark, PhD, Associate Professor, Medicinal Chemistry &Molecular Pharmacology, Purdue University
We present novel approaches for the selection of molecules from DNAencoded libraries (DEL) using enzymatic tags on target proteins. We apply
these assays for DEL discovery with GPCRs in live cells for both the discovery
of ligands and for specific discovery of biased agonists.

1:45 Welcome Remarks

5:15 Dinner Short Course Registration*

12:25 pm Enjoy Lunch on Your Own

1:50 Chairperson’s Remarks
Florence Brunel, PhD, Senior Principal Scientist, Novo Nordisk Inc

1:55 New NMR Applications for Quantitative Determination of GPCR
Drug Efficacy and Lead Compound Identification
Matthew T. Eddy, PhD, Assistant Professor, Chemistry, University of Florida,
Gainesville
We present a new application of NMR spectroscopy to quantitatively
determine GPCR drug efficacy. NMR data quantitatively correlate with resultsfrom cellular signaling assays. We highlight examples where the NMR method
proves particularly advantageous, especially in accurately quantifying efficacy
for compounds with lower potency. Additionally, we present a new approachthat leverages NMR to identify weakly interacting small molecule fragments
for GPCR drug discovery.

2:25 Bioorthogonal Tethering of Drug Fragments to Engineered
GPCRs
Jordan Mattheisen, PhD, Postdoctoral Fellow, Chemical Biology, AstraZeneca

31 | DiscoveryOnTarget.com*Premium Pricing or separate registration required. See Short Courses page fordetails.

5:15 Diversity Discussion (Sponsorship Opportunity Available)
IN-PERSON DISCUSSION: Fostering Diversity through Mentoring
Naytia Byrd, Manager, Human Resources, Ovid Therapeutics, Inc.
Saudat Fadeyi, PhD, MBA, Director, Business Development, Ovid
Therapeutics, Inc.
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics
Joel Omage, Research Scientist II, CVM Disease Area, Novartis Institutes
for BioMedical Research, Inc.
Andrew Zhang, PhD, Director, Chemical Biology, AstraZeneca
Topics for discussion will include, but certainly not be limited to:• How to increase awareness and address hidden barriers and biases inlife sciences• How to motivate early-career scientists to seek out mentors andresources• How to convince senior leadership to take time for coaching the next
generation of leaders and support DEI initiatives

Cambridge Healthtech Institute’s 19th Annual

GPCR-Based Drug Discovery

Targeting G Protein-Coupled Receptors for New Therapeutic Options
OCTOBER 2-3, 2024

• How to create simple and impactful opportunities for mentors andmentees to connect and collaborate​​

6:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

8:30 Close of Day
THURSDAY, OCTOBER 3

7:30 am Registration Open and Morning Coffee

This presentation will focus on the development of small molecule agonist
versions of peptide-binding GPCRs such as GLP-1R.

10:20 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Peptide Agonists for GPCRs

INSIGHTS FROM VENTURE CAPITALISTS
8:00 PANEL DISCUSSION: Trends in Drug Discovery

Moderator: Daniel A. Erlanson, PhD, Chief Innovation Officer, Innovation
and Discovery, Frontier Medicines Corporation
Panelists:
Jernej Godec, PhD, Principal, Atlas Venture
Jenna Hebert, PhD, Senior Associate, RA Capital Management
Jamie Kasuboski, PhD, Partner, Luma Group
Jasmina Marjanovic, PhD, Partner, Takeda Ventures
Swetha Murali, PhD, Vice President, OMX Ventures

STRUCTURE-BASED DRUG DESIGN FOR GPCRs
8:45 Chairperson’s Remarks
Susruta Majumdar, PhD, Associate Professor, Clinical Pharmacology, St. Louis
College of Pharmacy, University of Washington

8:50 Structure, Function, and Pharmacology of Delta Opioid
Receptor Ligands for the Development of Better Chronic Pain
Therapeutics
Sarah Bernhard, Laboratory of Susrata Majumdar, Center for ClinicalPharmacology, Washington University School of Medicine
Therapeutic options for treating chronic pain are limited by low efficacy
and adverse effects. Delta opioid receptor (DOR) agonists show potential inrelieving chronic pain symptoms; however, they can exhibit adverse effects
like seizures and tolerance. Our studies aim to understand pharmacologicaland behavioral profiles of DOR full agonists, partial agonists, and allostericmodulators to develop a structural platform for designing the next generationof pain relievers.

9:20 Discovery and Mechanism of Opioid Receptor Allosteric
Modulators
Evan O’Brien, PhD, Assistant Professor, Biophysics & Biophysical Chemistry,
The Johns Hopkins University School of Medicine
The mu-opioid receptor (MOR) is a well-established GPCR target for analgesia,
yet conventional orthosteric opioid agonists suffer from serious adverse
effects, notably respiratory depression and addiction. We screened a large
DNA-encoded chemical library and discovered new positive and negative
allosteric modulators of the receptor. We then used cryoEM to determine
detailed structural mechanisms of allosteric modulation and demonstrated invivo efficacy for a new class of “Narcan-boosters.”

9:50 Developing Small Molecule Agonists of GLP-1R and other
Peptide-Binding GPCRs

Florence Brunel, PhD, Senior Principal Scientist, Novo Nordisk Inc• How will small molecule GPCR agonists compete with peptides?
• What are the next GPCRs to be blockbusters?
• What is the limitation to developing more peptide GPCR agonists? What
are the new techniques to help solve these issues?​

IN-PERSON BREAKOUT: Innovations in GPCR-Hit Discovery
Evan O’Brien, PhD, Assistant Professor, Biophysics & Biophysical
Chemistry, The Johns Hopkins University School of Medicine• Role of cryoEM• Impact of AI• DNA-Encoded Libraries (DEL) & GPCRs• New biophysical tools: SPR microscopy, single-molecule FRET​

11:05 Coffee Break in the Exhibit Hall with Poster Viewing and Bestof Show Awards Announced

GPCR-TARGETED DRUG CANDIDATES
11:45 FEATURED PRESENTATION: Discovery of Clinical
Candidate AZD5462, an Allosteric Oral Small Molecule RXFP1
Agonist for the Treatment of Heart Failure

Niklas Larsson, PhD, Principal Scientist, AstraZeneca R&D
The relaxin H2 hormone is a clinically relevant peptide agonist for the
G protein-coupled receptor RXFP1, but the short half-life and needfor injectable delivery limits its therapeutic potential. AZD5462 is thefirst clinical candidate, small-molecule RXFP1 agonist that mimics thesignaling pharmacology of relaxin H2. AZD5462 is a promising potential
therapeutic treatment for patients with heart failure and other conditions
where physiological effects of chronic RXFP1 agonism are desirable.

12:15 pm Discovering the Next-Generation of GPCR-targeted
Therapeutics to Address Metabolic Diseases with Unmet Patient
Needs
Oliver Hartley, PhD, Vice President, Drug Discovery, Orion Biotechnology
I present how we leveraged a novel drug modality and proprietary discovery
platform to unlock metabolic GPCRs.This enabled us to advance a pipelineof differentiated therapeutics for obesity and metabolic disorders. We strive
to capture the untapped potential of novel metabolic targets with innovative
monotherapy & combination approaches.

12:45 Enjoy Lunch on Your Own
1:50 Dessert Break in the Exhibit Hall with Last Chance for Poster
Viewing

Yingli Y Ma, PhD, CTO, Platform Technology, Structure Therapeutics Shanghai
Basecamp Biotechnology Co

DiscoveryOnTarget.com | 32

Cambridge Healthtech Institute’s 8th Annual

Lead Generation Strategies
Small Molecule Drug Discovery Innovations | OCTOBER 1-2, 2024

GPCR-TARGETED DRUG CANDIDATES (CONT’D)
2:30 Chairperson’s Remarks
Yamina A. Berchiche, PhD, Founder, Dr. GPCR

2:35 Selecting a Clinical Candidate Based on GPCR Signaling
Profiles: Discovery of FPR2 Agonist BMS-986331
Nicholas R. Wurtz, PhD, Associate Director, Discovery Chemistry, Bristol Myers
Squibb Co.
Formyl Peptide Receptor 2 (FPR2) agonists with biased GPCR signaling
profiles were discovered through a combination of screening and rational
design. A detailed evaluation of these agonists demonstrated that a specificprofile afforded efficacy in rodent heart failure models. Optimization of an
arylpiperidinone chemotype with the preferred GPCR agonist profile led tothe identification of BMS-986331, which was progressed into Phase I clinical
trials.

3:05 Methodological Toolbox to Characterise Allosteric Modulators
at CB1R
Dmitry Veprintsev, Professor of Molecular & Cellular Pharmacology, Universityof Nottingham; Co-Founder and CEO, Z7 Biotech Ltd.
Allosteric ligands modulate receptor responses without completely blocking
their functions, an attractive property for drug development. However
characterizing allosteric modulators is challenging. We developed afluorescent allosteric probe which differentiated effects of orthosteric andallosteric ligands binding to the CB1 receptor. We further performed G protein
recruitment and ModuMelt™ assays to understand the pharmacologicalactivity and cooperativity of orthosteric and allosteric ligand binding. This
toolbox is applicable to other GPCRs

3:35 Structure-Based Drug Discovery on OX2R
Pieter Claes, PhD, Principal Scientist, Medicinal Chemistry, Confo Therapeutics
Agonism of the Orexin type 2 receptor has emerged as an attractive approachfor the treatment of narcolepsy. Here, we describe the identification of anagonist series [PC1] using a new screening assay based on ConfoBodies,
the elaboration of the chemical series and its puzzling structure-activity
relationship. Determination of the active-state structure with a series
representative revealed the cause of these unexpected activity cliffs.

4:05 Presentation to be Announced
4:35 Close of Conference

DiscoveryOnTarget.com | 33

Cambridge Healthtech Institute’s 12th Annual

Antibodies Against Membrane Protein Targets
New Strategies and Technologies to Accelerate the Development of
Biotherapeutics Against Complex GPCR and Ion Channel Targets
OCTOBER 1-2, 2024
TUESDAY, OCTOBER 1

7:00 am Registration Open and Morning Coffee

EMERGING MODALITIES
7:55 Welcome Remarks
8:00 Chairperson’s Remarks
Robbins Puthenveetil, PhD, Senior Scientist, AstraZeneca

8:05 Overcoming the Challenges with Raising Antibodies against
STEAP2 Extracellular Domains for Targeted CAR T Cell Therapy
Dewald van Dyk, PhD, Associate Director, Biologics Engineering, AstraZeneca
Pharmaceuticals LP
Six-transmembrane epithelial antigen of prostate-2 (STEAP2) is a complex
membrane protein that is highly expressed on prostate cancer cells withlimited distal normal tissue expression. High species homology and small
extracellular domains make STEAP2 a very challenging protein to target. I will
share reflections on the multifaceted discovery campaigns that enabled theisolation of STEAP2-specific antibodies for the development of an armored
STEAP2 chimeric antigen receptor T cell therapy.

8:35 Transferrin Receptor Targeting Chimeras (TransTACs) for
Targeted Depletion of Complex Membrane Targets
Kaitlin Rhee, Researcher, Xin Zhou Lab, Biological Chemistry & Molecular
Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School
GPCRs play critical roles in nearly all aspects of cancer progression, including
growth and survival, invasion and metastasis, and drug resistance. However,signaling inhibition can be complicated by ligand-independent signaling,oligomerization with coreceptors, multiple ligand and receptor pairings,
and the challenge of developing selective high-affinity antagonists. Thus,
we propose an induced proximity/bispecific antibody-based approach toselectively deplete GPCRs for sustained signaling inhibition, by co-opting
cancer cell-surface recycling and lysosome-targeting receptors.

9:05 Antibody-Drug Conjugates Targeting GPCRs and Combination
Strategies to Enhance Efficacy in Colorectal Cancer
Kendra Carmon, PhD, Associate Professor, Center for Translational Cancer
Research, University of Texas Health Science Center at Houston
Our group has generated antibody-drug conjugates (ADCs) directed against
G protein-coupled receptor (GPCR) targets highly expressed in colorectal andother cancer types. These GPCR-targeted ADCs were generally well-tolerated
and show promising efficacy in preclinical models of colorectal cancer, yettumors were not completely eliminated. Currently, we are evaluating ADCs in
combination with FDA-approved therapies to enhance efficacy and overcome
resistance and relapse.

9:35 Networking Coffee Break
10:05 Discovery and Engineering of Bispecific Anti-CD3 Heavy
Chain-Only Antibodies
Noel T. Pauli, PhD, Group Leader, Antibody Engineering, Adimab LLC
T cell engagers utilizing CD3 are an increasingly validated class ofmultispecific antibodies, but are inherently complicated to generate. Reducing
engineering complexity through a CD3-specific heavy chain–only antibody(HCAb) would be beneficial. Using a yeast-based platform, we demonstrate
the discovery and engineering of a panel of high-affinity, CD3-specific, HCAbs
from immunized camelids, and validate their use in functional bispecificmolecules.

34 | DiscoveryOnTarget.com

10:35 SPECIAL PRESENTATION: Insights from Current
Pipelines of Antibody-Based Therapeutics against GPCR, IonChannel, and Transporter Targets

Catherine Hutchings, PhD, Independent Consultant
Complex multi-pass transmembrane proteins represent some of themost important drug target classes across a wide range of therapeuticareas. An annual update on antibody-based therapeutics in the GPCR,
ion channel, and transporter R&D pipeline will be provided, outlining thebreadth and diversity of the target landscape.

11:05 KEYNOTE PRESENTATION: Insights from
Alphafold2 Antibody Screening against High-Value
GPCRs

Jeffrey Skolnick, PhD, Professor, Biology, Director, Center for
the Study of Systems Biology, Georgia Institute of Technology
Alphafold2Complex, a generalization of Alphafold2, can predict if
proteins interact, and if so, their quaternary structure. AF2Complex
has provided insights into important pathways such as the outermembrane biogenesis pathway in E. coli. Here, it is applied to theantibody modulation of GPCR signaling associated with breast cancer
cell migration. Following modeling the activation of GPCRs that initiate
breast cancer cell migration, we suggest antibodies that could inhibit
this process.

11:35 Structure-Based Charge Calculations for
Predicting Properties and Profiling Antibody
Therapeutics
Philippe Archambault, Application Scientist, Chemical Computing GroupWe present a method for modeling antibodies and performing pH-dependent
conformational sampling, which can enhance property calculations.
Structure-based charge descriptors are evaluated for their predictive
performance on recently published antibody pI, viscosity, and clearance data.
From this, we devised four rules for therapeutic antibody profiling which
address developability issues arising from hydrophobicity and charged-based
solution behavior, and PK.

12:05 pm Transition to Lunch
12:10 LUNCHEON PRESENTATION: Advanced Antigen
Design Strategies for Shaping Human Antibody
Repertoires in OmniAb Animals
Devendra Srivastava, Director, OmniAb
OmniAb antibody discovery campaigns leverage advanced immunization
strategies tailored for high-value, challenging targets, including ion channels,
GPCRs, and multi-pass transmembrane proteins. To shape robust immune
repertoires, we have developed proprietary mRNA-LNP production methods
and engineered vector libraries for rapid high-quality production of membraneproteins.

12:40 Session BreakDISCOVERY TOOLS AND TECHNOLOGIES
1:15 Chairperson’s Remarks
Catherine Hutchings, PhD, Independent Consultant

1:20 bioSens-All: A Multiparametric BRET-Based Platform for
Comprehensive Profiling of GPCR Signaling and PharmacologyEnabling Drug Discovery
Laurent Sabbagh, PhD, Scientific Director, Domain Therapeutics

Cambridge Healthtech Institute’s 12th Annual

Antibodies Against Membrane Protein Targets
New Strategies and Technologies to Accelerate the Development of
Biotherapeutics Against Complex GPCR and Ion Channel Targets
OCTOBER 1-2, 2024

The 3rd-generation bioSens-All platform combines BRET-based biosensors
that are highly adaptable to the needs of discovery projects for small
molecules, peptides, and antibodies. The platform has been successfully usedinternally to identify biased small molecule negative allosteric modulators forprotease-activated receptor 2 (PAR2). In addition, the platform was used todevelop assays for high-throughput screening for the challenging adhesion
GPCR, ADGRE5.

1:50 Application of Synthetic Libraries against Membrane Targets
for Antibody Generation
Jeffrey Barker, PhD, Principal Research Scientist, AbbVie
Discovery of biotherapeutics against challenging targets such as integral
membrane proteins, membrane protein complexes, and heavily glycosylated
surface proteins using display technologies remains a challenge. We have
utilized therapeutic-ready phage- and yeast-display platforms expressing
a diversity of formats to pan against both cells and virus-like particles.
Using these novel reagents and protocols, we have managed to discoverbiotherapeutics to traditionally display “unfriendly” targets.

2:20 Accelerating Biotherapeutics Development against
Membrane Proteins Using Next-Generation PolymersBased Nanodiscs
Jan Kubicek, CSO & Co Founder, Cube Biotech GmbH
Detergent solubilization is one of the biggest roadblocks against therapeutic
development for membrane proteins as they provide poor protein stabilizationand interfere with many downstream applications. I will discuss how copolymers can efficiently solubilize membrane proteins into native nanodiscs
which, unlike detergents, preserves the protein’s environment and function. I
will illustrate how co-polymer stabilization outperforms classical detergents indisplay and drug discovery techniques.

2:50 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Avoiding Roadblocks: Maneuvering the
Challenges of Difficult Targets
Joseph Rucker, PhD, Vice President, Research and Development, Integral
Molecular, Inc.

3:35 Grand Opening Refreshment Break in the Exhibit Hall with
Poster Viewing and Best of Show Voting Begins
4:35 Leveraging Structural Biology to Address Discovery Challenges
with Complex Membrane Proteins
Robbins Puthenveetil, PhD, Senior Scientist, AstraZeneca
Cryo-electron microscopy has revolutionized structural characterizationof complex membrane proteins, leading to improved design of powerfulbiologics. With the advent of cryo-EM, significant strides made throughstructure-based drug design approaches have augmented the specificity
and efficacy of therapeutic interventions. In this presentation, we will explore
the obstacles encountered by a multi-pass transmembrane protein target,
illustrating how cryo-EM can help overcome these challenges and instruct
remediation of liabilities though protein engineering.

5:05 Engineering a New Class of Therapeutic Proteins with
Antibody-Like Properties
Mahmoud Nasr, PhD, RPh, Assistant Professor, Medicine, Brigham and
Women’s Hospital, Harvard Medical School
We will introduce a new class of therapeutic proteins. Our newly engineered
proteins offer great advantages over the conventional antibodies andnanobodies. We will discuss their properties, their production, and finally,show their use to target membrane proteins implicated in various diseases.

5:35 Biology-Based ML Model for Targeting GPCR-Biased Signaling
CascadesAurelien Rizk, PhD, CSO & Co-Founder, InterAx Biotech AG
InterAx combines real-time cellular assays and mathematical pathway
modelling to define novel pharmacodynamic parameters. These parameters
quantify signaling and kinetic biases, allowing to (1) determine the optimal
signaling profile for therapeutic efficacy and safety and (2) apply machinelearning methods to efficiently select and optimize drugs. We will show how
we use this approach to discover diabetes and obesity drugs that minimize
nausea without compromising effectiveness.

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
7:05 Close of Day
WEDNESDAY, OCTOBER 2

7:30 am Registration Open and Morning Coffee

MACHINE LEARNING FOR GPCR BIOTHERAPEUTICS
7:55 Chairperson’s Remarks
Noel T. Pauli, PhD, Group Leader, Antibody Engineering, Adimab LLC

8:00 De novo Design and Engineering of Novel GLP1R Agonist
Miniprotein
Ben Meinen, PhD, Head, Protein Design, AI Proteins
De novo–designed miniproteins represent a groundbreaking new modality,
offering unprecedented flexibility in engineering biologics with an array ofdesirable features tailored for specific applications. We developed a novel
GLP1R-agonist miniprotein designed de novo to exhibit improved biased
signaling with a strong emphasis on G protein-coupled signaling, while
significantly reducing ß-arrestin signaling.

8:30 Rapid Screening for GPCR Active Ligands Using Machine
Learning
Jianing Li, PhD, Assistant Professor, Medicinal Chemistry and Molecular
Pharmacology, Purdue University
Molecules with bioactivity towards GPCRs represent a subset of the vast
space of small drug-like molecules. Machine learning models, including
dilated graph convolutional networks, have been created and validated forbinary classification to quickly identify active molecules towards GPCRs. As
proof of principle, the incorporation of our best model into a high-throughput
virtual screening workflow is demonstrated for several class A and class B
receptors.

9:00 GPCR-BERT: Interpreting Sequential Design of G ProteinCoupled Receptors Using Protein Language Models
Amir Barati Farimani, PhD, Associate Professor, Machine Learning, Carnegie
Mellon University

DiscoveryOnTarget.com | 35

Cambridge Healthtech Institute’s 12th Annual

Antibodies Against Membrane Protein Targets
New Strategies and Technologies to Accelerate the Development of
Biotherapeutics Against Complex GPCR and Ion Channel Targets
OCTOBER 1-2, 2024

We developed GPCR-BERT, a transformer-based model, to understand thesequential design of G protein-coupled receptors (GPCRs). By fine-tuning themodel with prediction tasks on conserved motifs, we elucidated relationships
between binding pocket residues and motifs. Attention weights and hidden
states were analyzed to determine amino acid contributions. Embedding
analysis over 3D structures revealed higher-order interactions within receptor
conformations. GPCR-BERT demonstrates the potential of language models intherapeutic design.

9:30 Sponsored Presentation (Opportunity Available)
10:00 Coffee Break in the Exhibit Hall with Poster Viewing

PLENARY KEYNOTE PROGRAM
10:50 Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Close of Antibodies Against Membrane Protein Targets
Conference

DiscoveryOnTarget.com | 36

Cambridge Healthtech Institute’s InauguralCancer Antibodies
Engineering, Targeting, and Efficacy: Optimizing Antibodies for Clinical Success
OCTOBER 2-3, 2024

WEDNESDAY, OCTOBER 2

PLENARY KEYNOTE PROGRAM
10:50 am Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

Xencor has developed a robust bispecific antibody platform based on a novel
set of Fc domain substitutions that promote high heterodimer yield and facile
purification. We’ll discuss application of this platform to the developmentof classic CD3 bispecific antibodies and CD28 costimulatory bispecifics.
The XmAb 2+1 format—enabling bivalent targeting of a tumor-associatedantigen and monovalent engagement of CD3—promotes higher tumor/normal
selectivity with growing clinical validation.

2:55 Sponsored Presentation (Opportunity Available)
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 Engineering a Novel IL-2-Based Immunocytokine with
Enhanced Effector and Memory Function
Anjali Shenoy, PhD, Post Doctoral Researcher, Molecular Biology &Immunology, John Hopkins University
We have previously developed therapeutic immunocytokines (IC) whichlink interleukin-2 (IL-2) to anti-cytokine antibodies that bias IL-2 towards
potentiating immune effector cells and promote tumor clearance. Here, we
engineered a novel immunocytokine which replaces IL-2 with a variant thatelicits memory-biased immune responses. The resulting molecule induces
both effector cell responses for tumor elimination and memory responses toprevent cancer reoccurrence, representing a powerful new strategy for cancer
treatment.

4:45 Optimizing Delivery and Half-Life of Small Antibodies
Vince Kelly, PhD, Graduate Research Assistant, Biochemistry, University of
Illinois
Here, we demonstrate that rational swapping of surface-exposed cationic
residues with anionic restudies, in combination with fusion to a homotrimeric
peptide domain, significantly extends half-life and delays renal filtration of
single-domain antibodies. Further, we combine these modifications with FcRnbinding peptide fusions to facilitate transmembrane transport in a mousemodel. These rational modifications may improve the suitability of nanobodies
for use as therapeutics, particularly in combination with alternative delivery
systems.

12:25 pm Enjoy Lunch on Your Own

5:15 Dinner Short Course Registration*

ENGINEERING ANTIBODIES FOR PRECISION IO*Premium Pricing or separate registration required. See Short Courses page fordetails.

1:45 Welcome Remarks

5:15 Diversity Discussion (Sponsorship Opportunity Available)

1:50 Chairperson’s Opening Remarks

IN-PERSON DISCUSSION: Fostering Diversity through Mentoring

Anjali Shenoy, PhD, Post Doctoral Researcher, Molecular Biology &Immunology, John Hopkins University

1:55 Selective Targeting of Oncogenic Hotspot Mutations of the
HER2 Extracellular Region
Injin Bang, PhD, Postdoctoral Researcher, Infectious Diseases & Immunology,
New York University
We developed antibodies exquisitely selective to HER2 S310F/Y, two of themost common oncogenic mutations in the HER2 extracellular region. Cryo-EM
structures reveal that these antibodies mimic the dimerization arm of HER andinhibit dimerization. As T cell engagers, they selectively killed a HER2 S310Fdriven cancer cell line in vitro and in a mouse xenograft model. Overall, these
antibodies appear to be promising candidates for clinical development.

2:25 A Robust Heterodimeric Fc Platform Engineered for Efficient
Development of Bispecific Antibodies of Multiple Formats
John R. Desjarlais, PhD, CSO, Xencor

Naytia Byrd, Manager, Human Resources, Ovid Therapeutics, Inc.
Saudat Fadeyi, PhD, MBA, Director, Business Development, Ovid
Therapeutics, Inc.
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics
Joel Omage, Research Scientist II, CVM Disease Area, Novartis Institutes
for BioMedical Research, Inc.
Andrew Zhang, PhD, Director, Chemical Biology, AstraZeneca
Topics for discussion will include, but certainly not be limited to:• How to increase awareness and address hidden barriers and biases inlife sciences• How to motivate early-career scientists to seek out mentors andresources• How to convince senior leadership to take time for coaching the next
generation of leaders and support DEI initiatives• How to create simple and impactful opportunities for mentors andmentees to connect and collaborate​​

6:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

37 | DiscoveryOnTarget.com

Cambridge Healthtech Institute’s InauguralCancer Antibodies
Engineering, Targeting, and Efficacy: Optimizing Antibodies for Clinical Success
OCTOBER 2-3, 2024

8:30 Close of Day
THURSDAY, OCTOBER 3

7:30 am Registration Open and Morning Coffee

ENGINEERING ANTIBODIES FOR PRECISION IO
8:00 Chairperson’s Remarks
Francis Gaudreault, PhD, Research Officer, Human Health Therapeutics,
National Research Council Canada

8:05 Maleimides in Site-Specific Antibody Conjugations Creating
Two Carbon-Carbon Bonds Using an Enzyme and a 100-Year-Old
Reaction
Thomas Nittoli, PhD, Senior Director, Therapeutic Proteins, R&D Chemistry,
Regeneron Pharmaceuticals, Inc.
We present a two-step sequential conjugation approach that marries the site
specificity of the bacterial transglutaminase (TG) reaction with the robustness
of Diels-Alder (DA) chemistry to generate stable antibody conjugates. In
addition, we show strong potency of antibody conjugates, prepared via
TG-DA chemistry, in both cell-based assays and a mouse model. Overall, ourconjugation approach is site specific, versatile, and stable.

FROM SEQUENCING TO STRUCTURE: CUTTING-EDGECOMPUTATIONAL TOOLS
8:50 Rapid Discovery of High-Affinity Antibodies via Massively
Parallel Sequencing, Ribosome Display, and Affinity Screening
Christopher Wassif, PhD, Director, Molecular Engineering & Antibody
Technologies, AstraZeneca
This presentation will focus on the convergence of a new high-throughput
antibody discovery platform capable of screening 100s of millions ofantibodies with machine learning to accelerate the full discovery process. This
work is resulting in the identification of high-affinity, developable modalities
fit for therapeutic use in accelerated time frames, while generating significant
amounts of data and further refining our algorithms and models.

9:20 Structural Basis of Antibody Conformation and Stability
Modulation by Framework Somatic Hypermutation
Zizhang Sheng, PhD, Assistant professor, Aaron Diamond AIDS ResearchCenter, Columbia University
Accumulation of somatic hypermutation (SHM) is the primary mechanism toenhance the binding affinity of antibodies to antigens in vivo. Here, we built
a high-throughput structural bioinformatics pipeline to study the effects of
SHMs on antibody conformation, flexibility, stability, and affinity. Our study
revealed a common mechanism of antibody conformation and stability
modulation by framework mutations and epistatic effects between framework
SHMs.

9:50 KEYNOTE PRESENTATION: Antibody-Antigen
Structure Prediction from Deep Learning-Generated
ModelsFrancis Gaudreault, PhD, Research Officer, Human Health
Therapeutics, National Research Council Canada
The prediction of the structure of antibody-antigen complexes in silico
would provide a lot of value for medical applications. Recent deeplearning technologies have enabled the production of antibody models
with significantly better quality than traditional tools. We evaluatedif such quality is sufficient for successful antibody-antigen structure
prediction, using traditional molecular docking tools that normally fallshort in real applications where the antibody structure is unknown.

10:20 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Strategies for Enhancing Antibody
Efficiency and Selectivity
Thomas Nittoli, PhD, Senior Director, Therapeutic Proteins, R&D
Chemistry, Regeneron Pharmaceuticals, Inc.
• Improving tissue penetration and targeting• Reducing immunogenicity and off-target effects• Optimizing antibody-drug conjugate design and development​

11:05 Coffee Break in the Exhibit Hall with Poster Viewing and Bestof Show Awards Announced
11:45 Antibody Mutations Favoring pH-Dependent Binding in Solid
Tumor Microenvironments: Insights from Large-Scale StructureBased Calculations
Wanlei Wei, PhD, Research Associate, Computer-Aided Drug Discovery,
National Research Council Canada
In recent years, engineering of pH-sensitive therapeutic antibodies has
gained traction, for endosomal recycling and enhanced specificity in acidic
solid-tumor microenvironments. While there is a need for pH-dependent
immunotherapies, current engineering techniques are tedious and laborious,
requiring repeated rounds of experiments under different pH conditions.
Here, we developed a sequence-based method for engineering pH-dependent
antibody binders, called SIpHAB, which could circumvent the lack of structuraldetails.

BRINGING TARGETED DELIVERY TO THE CLINIC
12:15 pm Harnessing Modular E3 Ligase and Cytokine Receptor
Targeting Chimeras to Degrade Cell-Surface and ExtracellularProteins
Josef Gramespacher, PhD, Co-Founder, EpiBiologics
By ablating all disease-associated functions of a given protein at once,
targeted protein degradation has emerged as a promising therapeutic strategy
to overcome limitations of traditional occupancy-based inhibitors. To this end,
at EpiBiologics we are developing antibody-based PROTACs (AbTACs) andcytokine receptor-targeting chimeras (KineTACs). These are fully recombinant
and modular bispecific antibodies capable of recruiting membrane-boundE3 ligases or cytokine receptors to mediate degradation of cell-surface andextracellular proteins.

12:45 Sponsored Presentation (Opportunity Available)
1:15 Transition to Lunch
1:20 Luncheon Presentation (Sponsorship Opportunity Available) or
Enjoy Lunch on Your Own
1:50 Dessert Break in the Exhibit Hall with Last Chance for Poster
Viewing

DiscoveryOnTarget.com | 38

Cambridge Healthtech Institute’s InauguralCancer Antibodies
Engineering, Targeting, and Efficacy: Optimizing Antibodies for Clinical Success
OCTOBER 2-3, 2024

BRINGING TARGETED DELIVERY TO THE CLINIC(CONT.)
2:30 Chairperson’s Remarks
John R. Desjarlais, PhD, CSO, Xencor

2:35 Delivery of a Therapeutic Bispecific T Cell Engager Using a pHSensitive Nanoparticle Platform
Tian Zhao, PhD, Vice President, R&D, OncoNano Medicine
Spatially and temporally precise delivery of therapeutic macromolecules—
such as bispecific T cell engagers—to tumors, while avoiding systemic
toxicity, remains a challenge in transforming cancer treatment. OncoNano
is developing the ON-BOARD ultra-pH sensitive micelle delivery platform
to surmount these constraints. Herein, we report the efficacious masked
delivery of a bispecific T cell engager to tumors in mice using ON-BOARD,
demonstrating an improved safety profile and potential for clinical translation.

3:05 Tumor-Activated, Fc-Enhanced CTLA-4 Antibody XTX101
Demonstrated Potent Tumor-Growth Inhibition and Tumor-Selective
Pharmacodynamics in Vivo
Kurt Jenkins, PhD, Director, Xilio Therapeutics
The clinical benefit of CTLA-4 blocking antibodies has been well establishedbut treatment-related toxicities remain a limiting factor. XTX101 is aninvestigational tumor-activated, Fc-enhanced, high affinity binding antiCTLA-4 monoclonal antibody designed to maximize activity in the tumor
microenvironment and improve tolerability compared with systemically
active anti-CTLA-4 antibodies. This talk will cover design and preclinicalcharacterization of XTX101, including demonstration of tumor regressions
and tumor-specific pharmacodynamic changes in vivo.

3:35 Discovery and Development of DYP688
John W. Blankenship, PhD, Executive Director and Head, Biologics Discovery
and Automation, Novartis Biomedical Research
GNAQ/11 mutations occur in up to 95% of uveal melanomas and areconsidered genetic drivers of the disease. PMEL17 (gp100) is a melanocytic
lineage gene that is highly and broadly expressed in melanomas. DYP688
is a novel antibody-drug conjugate that binds to PMEL17 on target cells todeliver the payload SDZ475, a targeted inhibitor of Gq/11 oncogenic signaling.
Preclinical and early clinical development of DYP688 will be discussed.

4:05 PANEL DISCUSSION: Delivering Cancer Antibodies to the Clinic
Moderator: John W. Blankenship, PhD, Executive Director and Head, Biologics
Discovery and Automation, Novartis Biomedical Research
Panelists:
Josef Gramespacher, PhD, Co-Founder, EpiBiologics
Kurt Jenkins, PhD, Director, Xilio Therapeutics
Tian Zhao, PhD, Vice President, R&D, OncoNano Medicine

4:35 Close of Conference

DiscoveryOnTarget.com | 39

Cambridge Healthtech Institute’s 6th Annual

Small Molecules Targeting RNA
Identifying New Small Molecule Modalities and RNA Moieties for
Therapeutic Intervention | OCTOBER 1-2, 2024

TUESDAY, OCTOBER 1

7:00 am Registration Open and Morning Coffee

CHEMICAL BIOLOGY STRATEGIES FOR MODULATING
RNA
7:55 Welcome Remarks
8:00 Chairperson’s Remarks
Ken Hsu, PhD, Stephen F. and Fay Evans Martin Endowed Associate Professor,
Department of Chemistry, The University of Texas at Austin

8:05 Strategies to Modulate the Conformation and Function of RNA
with Small Molecules
Amanda Hargrove, PhD, Professor, Department of Chemistry, Duke University
The Hargrove Lab leverages fundamental discoveries of the drivers of small
molecule : RNA recognition to develop new strategies for RNA targeting.
These methods account for differences in RNA chemical and conformational
space to yield functional RNA-targeting small molecules and allow rational
optimization without high-resolution structure.

8:35 Chemical Approaches to Study and Target Post-transcriptional
RNA Regulatory Mechanisms
Ralph Kleiner, PhD, Assistant Professor, Department of Chemistry, Princeton
University
The Kleiner lab develops chemical approaches to study RNA modifying
enzymes and RNA-protein interactions. Here we will describe RNA-mediatedactivity-based protein profiling (RNABPP), a chemoproteomic strategy forprofiling and inhibiting RNA modifying enzymes using mechanism-based
modified nucleotide probes. We will also discuss TRIBE-ID, an RNA editingbased platform for studying RNA-protein interactions with temporal resolution.

9:05 Targeted Post-Translational Lysine Acetylation Modulates Viral
RNA-Host Protein Interactions
Mikail Abbasov, PhD, Assistant Professor, Chemistry and Chemical Biology,
Cornell University
The Abbasov laboratory exploits reactivity of lysines at RNA-protein
interaction interfaces by leveraging activity-based proteomics and lysinereactive natural products and small molecules. We developed activity-based
acylome profiling, a chemoproteomic strategy that exploits elaborate
acylating agents and lysine-centric probes for site-specific introduction andproteome-wide mapping of posttranslational lysine acylations in live cells.
We identified paralog-selective chemical probes that acetylate lysines ininterferon-stimulated antiviral RNA-binding proteins, generating proteoforms
with obstructed RNA interactions.

9:35 Networking Coffee Break
10:05 Covalent Targeting of Disease-Relevant RNA-Binding Proteins
Brahma Ghosh, PhD, Senior Principal Scientist & Head, Chemical Biology,
Global Discovery Chemistry, Johnson & Johnson
Here, I will present our efforts that led to the identification of covalent ligandsthat alter RNA-protein complexes in human cells. The talk will focus on the
discovery of novel chemotypes that stereo-selectively i) engage the RNAbinding protein NONO to decrease the expression of transcripts encoding theandrogen receptor and its splice variants in prostate cancer cells, and ii) thosethat functionally remodel the spliceosome to perturb mRNA splicing.

40 | DiscoveryOnTarget.com

10:35 PANEL DISCUSSION: Finding the Right Tools and Assays
to Study RNA Structure and Function

Moderator: Ken Hsu, PhD, Stephen F. and Fay Evans Martin Endowed
Associate Professor, Department of Chemistry, The University of Texas atAustinPanelists:
Mikail Abbasov, PhD, Assistant Professor, Chemistry and Chemical
Biology, Cornell University
Brahma Ghosh, PhD, Senior Principal Scientist & Head, Chemical Biology,
Global Discovery Chemistry, Johnson & Johnson
Amanda Hargrove, PhD, Professor, Department of Chemistry, Duke
University
Ralph Kleiner, PhD, Assistant Professor, Department of Chemistry,
Princeton University

11:35 Sponsored Presentation (Opportunity Available)
12:05 pm Transition to Lunch
12:10 Luncheon Presentation (Sponsorship Opportunity Available) or
Enjoy Lunch on Your Own
12:40 Session BreakAI FOR RNA DRUG DISCOVERY
1:15 Chairperson’s Remarks
1:20 Combining NMR Transverse Relaxation Times (T2) andComputational Chemistry to Target RNA
Barak Akabayov, PhD, Professor, Department of Chemistry, Ben Gurion
University of the Negev
Using a unique combination of NMR and computational chemistry, we havedeveloped novel antibacterial small molecules by targeting an RNA hairpin
within the ribosomal PTC. The optimization models used a dataset of small
molecules, and their docking scores were crucial in establishing designprinciples for new small molecules with improved bioactivity. We synthesizedmolecules, tested their ability to inhibit the ribosome, and demonstrated thebinding mechanism to the RNA hairpin.

1:50 LightON mRNA: Anima’s mRNA Lightning Brings AI to mRNA
Biology
Generoso Ianniciello, Chief Business Officer, Anima Biotech
Using high-content, high-throughput imaging, we have generated over 2 billion
visualizations to train our mRNA image neural network to identify diseasesignatures. Our massively parallel automated mRNA lab tests thousands ofmolecules, identifying active ones that visually restore diseased cells to theirhealthy state. MOAi technology utilizes the mRNA knowledge graph, our LLM,
and the Lightning co-pilot, rapidly pinpointing mechanisms of action andmolecular targets, through a unified, scalable interface.

2:20 Presentation to be Announced
2:50 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromCambridge Healthtech Institute’s 6th Annual

Small Molecules Targeting RNA
Identifying New Small Molecule Modalities and RNA Moieties for
Therapeutic Intervention | OCTOBER 1-2, 2024

your work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Challenges and Opportunities in
Pursuing RNA as a Drug Target

Generoso Ianniciello, Chief Business Officer, Anima Biotech
Karthik Iyer, PhD, Director, Head of Medicinal Chemistry, Arrakis
Therapeutics
Marla Weetall, PhD, Senior Vice President, Pharmacology and Biomarkers,
PTC Therapeutics

3:35 Grand Opening Refreshment Break in the Exhibit Hall with
Poster Viewing and Best of Show Voting Begins
4:35 Recent Advances in the Discovery of RNA-Targeted Small
Molecules
Karthik Iyer, PhD, Director, Head of Medicinal Chemistry, Arrakis Therapeutics
Our mission at Arrakis is to solve very broadly the problem of how to drug RNA
with small molecules. This presentation will provide an update on the platform
we have built to achieve that mission and provide early data on specific mRNAtargets.

5:05 Developing RNA-Targeted Oral Small Molecules to Treat
Incurable Diseases
Chris M. Yates, Executive Director, Head, Medicinal Chemistry, Rgenta
Therapeutics
Rgenta Therapeutics is leveraging our proprietary, integrative RNA-targetingsmall molecule discovery platform to pioneer the development of first-in-classoral therapies. Rgenta is pursuing oncology and neurological disease targets,
exemplified by the oncogenic transcription factor target c-MYB and the
PMS1 gene. PMS1 is a key component of the DNA mismatch repair pathway,
implicated in the pathological somatic trinucleotide repeat expansion
observed in Huntington’s Disease (HD) and other trinucleotide repeat
expansion disorders.

5:35 Targeting Pre-mRNA with Small Molecules
Marla Weetall, PhD, Senior Vice President, Pharmacology andBiomarkers, PTC Therapeutics
Utilizing small molecules to modulate splicing is a successful
therapeutic approach to regulate protein expression. EvrysdiTM (risdiplam)
was recently approved for the treatment of Spinal Muscular Atrophy. PTC518
is in clinical development for Huntington’s disease. The learnings from the
SMA and HD programs have helped PTC Therapeutics find other moleculesfor other diseases. Here, we discuss discovery, preclinical, and clinicaldevelopment of small molecules that modulate pre-mRNA.

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
7:05 Close of Day
WEDNESDAY, OCTOBER 2

7:30 am Registration Open and Morning Coffee

EXPLOITING EMERGING RNA BIOLOGY
7:55 Chairperson’s Remarks
Donny Licatalosi, PhD, Head, RNA Biology, Takeda Pharmaceutical Company

8:00 Pancreatic Cancer Cells Are Addicted to Expression of the
PLAC8 mRNA, but Not the Encoded Protein
Malte Buchholz, PhD, Head of Basic Research, Clinic for Gastroenterology,
Philipps University Marburg
The PLAC8 gene is strongly ectopically expressed in pancreatic ductal
adenocarcinoma (PDAC), and inhibition of PLAC8 expression significantly
impairs cell proliferation and viability. Surprisingly, the functional entity
mediating the cell-intrinsic pro-tumorigenic effects is not the PLAC8 protein,but instead the PLAC8 mRNA itself. Functionally, the PLAC8 mRNA, but not
the protein, is centrally important for maintenance of genome integrity (andhence cell viability) via regulation of the MRN complex.

8:30 Targeting an Oncogenic Long Noncoding RNA with Small
Molecule Compounds
Tao Liu, PhD, Associate Professor and Research Group Leader, Gene
Dysregulation Group, Children’s Cancer Institute Australia, University of New
South Wales
We have identified a novel long noncoding RNA, lncNB1, as a critical driver ofneuroblastoma progression in mouse models and identified the oncogenic
RNA-binding protein MSI2 as a functional partner binding protein of lncNB1.
Small molecule compound library screening identified SM2023 as an efficientinhibitor of lncNB1 RNA and MSI2 protein interaction. Treatment with SM2023
blocked lncNB1 and MSI2 function and induced neuroblastoma cell growth
inhibition and apoptosis.

9:00 Small Molecule-regulated Gene Therapy Using an Engineered
Small Molecule-binding Splice Site
Samie Jaffrey, MD, PhD, Professor, Department of Pharmacology, Weill Cornell
Medicine; Co-Founder, Gotham Therapeutics
We present Cyclone, a novel acyclovir-controlled poison exon systemdesigned for small molecule control of endogenous gene expression. By
engineering the exon 7 hairpin structure from SMN1 to include an acyclovirbinding aptamer, we enable tunable, reversible, and dynamic regulation of bothtransgenes and endogenous genes. Cyclone offers a streamlined approach tocontrolling gene expression, harnessing naturally occurring RNA structures for
efficient small molecule modulation.

9:30 Presentation to be Announced
9:45 Sponsored Presentation (Opportunity Available)
10:00 Coffee Break in the Exhibit Hall with Poster Viewing

PLENARY KEYNOTE PROGRAM
10:50 Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormones

DiscoveryOnTarget.com | 41

Cambridge Healthtech Institute’s 6th Annual

Small Molecules Targeting RNA
Identifying New Small Molecule Modalities and RNA Moieties for
Therapeutic Intervention | OCTOBER 1-2, 2024

is providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Close of Small Molecules Targeting RNA Conference

DiscoveryOnTarget.com | 42

Cambridge Healthtech Institute’s 2nd Annual

Targeting Transcription Factors

Innovative Chemistries and Assays for Increasing Druggability ofTranscription Factors | OCTOBER 2-3, 2024

WEDNESDAY, OCTOBER 2

PLENARY KEYNOTE PROGRAM
10:50 am Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

2:25 FEATURED PRESENTATION: An ‘Omics Approach
to Drug Discovery’

Liron Bar-Peled, PhD, Associate Professor, Medicine, Harvard
Medical School and Massachusetts General Hospital Cancer
CenterHow different oncogenic contexts influence cysteine targeting remains
unknown. To address this question, we have developed DrugMap, anatlas of cysteine ligandability compiled across 416 cancer cell lines.
Leveraging these findings, we identify actionable cysteines in SOX10 anddevelop corresponding covalent ligands. We demonstrate the SOX10
ligand increases SOX10-SOX10 interactions and disrupts melanoma
transcriptional signaling. Our findings illustrate the use of covalentprobes to disrupt oncogenic transcription factor activity.

2:55 Sponsored Presentation (Opportunity Available)
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing

EMERGING TRANSCRIPTIONAL MODULATORS
4:15 Innovative Strategies to Develop Pathway-Biased Small
Molecule Transcriptional Modulators
Nava Krishnan, PhD, Associate Research Fellow, Primary Pharmacology Group,
Pfizer Inc.
Transcriptional regulators are promising but challenging targets for drug
discovery and development. Dynamic conformational changes, a highdegree of intrinsic disorder in structure, and multiple binding partners
pose challenges to identify functional binders. In addition, transcriptional
modulators could regulate several downstream pathways by controlling gene
expression. Here, I will discuss multiple strategies taken to identify pathwayspecific biased modulators to impact a specific signaling pathway.

4:45 WDR5 WIN Site Inhibitors for Cancer Therapy

TRANSCRIPTIONAL CROSSTALK

William Tansey, PhD, Ingram Professor of Cancer Research, Professor of Cell &Development Biology, Vanderbilt University
WDR5 is a co-factor for MYC oncoprotein transcription factors and an
auspicious target for anti-cancer drug development. We have discovered
small molecule inhibitors of the “WIN” site of WDR5 that are highly potent,orally bioavailable, and active against multiple cancer types in preclinicalstudies. I will discuss our recent efforts to define the optimal strategies for
implementation of WIN site inhibitors for the future treatment of solid andhematologic malignancies.

1:50 Chairperson’s Remarks

5:15 Dinner Short Course Registration*

12:25 pm Enjoy Lunch on Your Own
1:45 Welcome Remarks

Asad Taherbhoy, PhD, Director, Drug Discovery, Foghorn Therapeutics

1:55 FEATURED PRESENTATION: Biochemical andFunctional Interplay Between Cancer-associatedmSWI/SNF Chromatin Remodeling Complexes andTranscription Factors

Cigall Kadoch, PhD, Associate Professor, Pediatric Oncology, Dana-Farber
Cancer Institute/Harvard Medical School; Scientific Founder, Foghorn
Therapeutics
ATP-dependent chromatin remodeling complexes are multi-component
molecular machines that govern genomic accessibility and gene
expression and are among the most frequently implicated cellular
entities in human cancer. This presentation highlights biochemical andstructural advances that have enabled the mechanistic understanding ofmSWI/SNF complex activities in normal and disease states, opening newopportunities for therapeutic intervention.

43 | DiscoveryOnTarget.com*Premium Pricing or separate registration required. See Short Courses page fordetails.

5:15 Diversity Discussion (Sponsorship Opportunity Available)
IN-PERSON DISCUSSION: Fostering Diversity through Mentoring
Naytia Byrd, Manager, Human Resources, Ovid Therapeutics, Inc.
Saudat Fadeyi, PhD, MBA, Director, Business Development, Ovid
Therapeutics, Inc.
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics
Joel Omage, Research Scientist II, CVM Disease Area, Novartis Institutes
for BioMedical Research, Inc.
Andrew Zhang, PhD, Director, Chemical Biology, AstraZeneca
Topics for discussion will include, but certainly not be limited to:• How to increase awareness and address hidden barriers and biases inlife sciences• How to motivate early-career scientists to seek out mentors andresources

Cambridge Healthtech Institute’s 2nd Annual

Targeting Transcription Factors

Innovative Chemistries and Assays for Increasing Druggability ofTranscription Factors | OCTOBER 2-3, 2024

• How to convince senior leadership to take time for coaching the next
generation of leaders and support DEI initiatives• How to create simple and impactful opportunities for mentors andmentees to connect and collaborate​​

6:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

8:30 Close of Day
THURSDAY, OCTOBER 3

7:30 am Registration Open and Morning Coffee

INSIGHTS FROM VENTURE CAPITALISTS
8:00 PANEL DISCUSSION: Trends in Drug Discovery

Moderator: Daniel A. Erlanson, PhD, Chief Innovation Officer, Innovation
and Discovery, Frontier Medicines Corporation
Panelists:
Jernej Godec, PhD, Principal, Atlas Venture
Jenna Hebert, PhD, Senior Associate, RA Capital Management
Jamie Kasuboski, PhD, Partner, Luma Group
Jasmina Marjanovic, PhD, Partner, Takeda Ventures
Swetha Murali, PhD, Vice President, OMX Ventures

a goldilocks range of reactivity to identify selective hits. Screening our library
has led to the identification of ligands for 40% of the proteome, including
functional ligands for undrugged transcription factors.

10:20 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: Leveraging Novel Strategies forTranscription Factors and Undruggable Targets

Kristy Stengel, PhD, Assistant Professor, Department of Cell Biology,
Albert Einstein College of Medicine
Asad Taherbhoy, PhD, Director, Drug Discovery, Foghorn Therapeutics
William Tansey, PhD, Ingram Professor of Cancer Research, Professor of
Cell & Development Biology, Vanderbilt University
Pamela Ting, PhD, Associate Director, Hematology, Novartis Institutes for
BioMedical Research

11:05 Coffee Break in the Exhibit Hall with Poster Viewing and Bestof Show Awards Announced

CHEMOPROTEOMIC & COVALENT APPROACHESSCREENING APPROACHES

8:45 Chairperson’s Remarks

11:45 Screening DNA Binding Proteins with DNA Encoded Libraries

Alexander Federation, PhD, Co-Founder & CEO, Talus Bioscience

8:50 Discovery and Optimization of Transcription Factor Modulators
Using Cell-Based, Functional Chemoproteomics
Alexander Federation, PhD, Co-Founder & CEO, Talus Bioscience
Previously “undruggable” transcription factors tend to fold and function
properly only within native cellular environments. To address these targets,
we developed TF-Scan, a live-cell assay that measures changes in TF DNAbinding activity after small molecule treatment. Using TF-Scan, we discovered
covalent compounds capable of binding and inhibiting dozens of previously
undruggable TFs. This was followed by rapid optimization of a lead brachyury
inhibitor that blocks chordoma tumor growth in vivo.

9:20 In-Cell Ligand Discovery for Challenging Targets Using AlkyneBearing Electrophiles
Lynn McGregor, PhD, Senior Principal Scientist, Novartis BioMedical Research
For many difficult-to-drug targets, the milieu of the native cellular environmentis critical to capturing the relevant biological state for ligand discovery. Alkynebearing electrophiles offer a flexible toolset for in-cell assay development,
including both mass spectrometry (MS)-based and non-MS based approaches
toward binder discovery for transcription factors and beyond.

9:50 ML-Guided Covalent Library Design Informed by Activity-Based
Protein Profiling Accelerates Hit-ID in Lead-Like Space
Adam Schwaid, PhD, Director, Chemical Biology & Proteomics, Odyssey
Therapeutics
Covalent molecules can target proteins once considered undruggable,
sparking renewed interest in covalency. Odyssey has built a lead-like covalentlibrary characterized by live-cell ABPP to determine binding and selectivity.
These measurements inform ML models, guiding library expansion towards

Christopher B. Phelps, PhD, Vice President and Head, Early Discovery, Nurix
Therapeutics, Inc.
Transcription factors are historically a challenging target class to drug.
Although DNA-encoded libraries (DEL) have become a staple for ligand
discovery, transcription factors and other proteins that specifically bind DNA
present distinct challenges for DEL technology. Nurix has developed a broadly
applicable approach for applying affinity selection and informatic methods totranscription factors, and these methods have yielded tractable hits for the
EWS-FLI1 fusion oncoprotein.

12:15 pm Small Molecule Inhibition of a TF-BAF Protein-Protein
Interaction in Cancer
Asad Taherbhoy, PhD, Director, Drug Discovery, Foghorn Therapeutics
Transcription factors (TFs) make for compelling drug targets but have been
historically hard to drug. In disease settings, TFs can hijack the BAF chromatin
remodeling complex to open incorrect regions of the genome, promoting
the diseased state. Here we highlight how Foghorn’s transcription factor
platform has been set up to understand TF-BAF interactions, develop various
HTS assays, and find chemical matter for the disruption of protein-protein
interactions.

12:45 Sponsored Presentation (Opportunity Available)
1:15 Transition to Lunch
1:20 Luncheon Presentation (Sponsorship Opportunity Available) or
Enjoy Lunch on Your Own
1:50 Dessert Break in the Exhibit Hall with Last Chance for Poster
Viewing

DiscoveryOnTarget.com | 44

Cambridge Healthtech Institute’s 2nd Annual

Targeting Transcription Factors

Innovative Chemistries and Assays for Increasing Druggability ofTranscription Factors | OCTOBER 2-3, 2024

DEGRADING TRANSCRIPTION FACTORS
2:30 Chairperson’s Remarks
Kristy Stengel, PhD, Assistant Professor, Department of Cell Biology, Albert
Einstein College of Medicine

2:35 Targeted Transcription Factor Degradation Reveals Therapeutic
Vulnerabilities and Mechanisms of Regulation
Kristy Stengel, PhD, Assistant Professor, Department of Cell Biology, Albert
Einstein College of Medicine
Transcription factors (TFs) are among the most frequently mutated and/ortranslocated genes in cancer, suggesting that a detailed understanding of theirmechanism-of-action could better define disease etiology and help identify
novel nodes for therapeutic intervention. Recently, our lab has employed novel
degron technologies to rapidly degrade TF proteins. This technology, whencombined with nascent transcript sequencing and multiomic readouts, allows
us to identify direct mechanisms of TF action.

3:05 Discovery of Highly Potent, Selective, and Efficacious STAT3PROTAC Degraders Capable of Achieving Long-Lasting Tumor
Regression
Haibin Zhou, PhD, Associate Research Scientist, Laboratory of Dr. Shaomeng
Wang, Department of Hematology & Oncology, University of Michigan
STAT3 is a transcription factor and a promising therapeutic target for cancer
and other human diseases. We have discovered a highly potent, selective,and efficacious STAT3 degrader UM-STAT3-1218. UM-STAT3-1218 is a highly
promising STAT3 degrader for the treatment of human cancers and otherhuman diseases in which STAT3 plays a key role.

3:35 Novel Heterobifunctional Modalities for Targeted Protein
Degradation and Stabilization
H. Ümit Kaniskan, PhD, Associate Professor, Laboratory of Dr. Jian Jin,
Department of Pharmacological Sciences, Icahn School of Medicine at Mt.
Sinai
The Jian Jin Laboratory at Icahn School of Medicine at Mount Sinai is aleader in discovering novel degraders targeting oncogenic proteins anddeveloping new technologies for advancing targeted protein degradation andstabilization. Our lab’s recent progress will be presented featuring our latest
studies such as Methyl-PROTAC, Z-PROTAC, and more.

4:05 Degradation of Nuclear Receptors for Oncology: AR Degrader
HP518 and ER Degrader HP568
Wu Du, PhD, Senior Vice President, Department of Medicinal Chemistry, Hinova
Pharmaceuticals, Inc.
Hinova discovered highly potent and orally available AR degrader HP518 andER-targeting degrader HP568. HP518 demonstrated an excellent preclinicalprofile and is currently in Phase I/II clinical trial. Thus far, HP518 has showeda satisfactory safety profile and encouraging efficacy signals in heavily
pretreated prostate cancer patients. HP568 showed oral PK and preclinicalefficacy superior to current leading AR degraders. Both compounds arepromising best-in-class AR and ER degraders.

4:35 Close of Conference

DiscoveryOnTarget.com | 45

Cambridge Healthtech Institute’s 3rd Annual

AI/ML-Enabled Drug Discovery – Part 1
Leveraging GenAI to Improve Speed, Efficiency and Effectiveness
OCTOBER 1-2, 2024

TUESDAY, OCTOBER 1

7:00 am Registration Open and Morning Coffee

AI FOR DRUG DESIGN & OPTIMIZATION
7:55 Welcome Remarks
8:00 Chairperson’s Remarks
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics

8:05 AI and Lab Automation to Move from Launch to IND in Two
Years: Discovering IAM1363, a Pan-Mutant, Brain-Penetrant HER2
Inhibitor
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics
I’ll describe the main elements of our AI-driven experimental platform(including models like NeuralPLexer for structure prediction, and plate-based
experimentation for closed-loop exploration and data generation). As an
example of how these technologies have been effectively brought to bear indiscovery projects at Iambic, I’ll talk through our lead program, which wentfrom launch to IND in 24 months, and is now being studied in a Phase 1
clinical trial.

8:35 Leveraging ML- and Physics-Based Methods for Design,
Optimization, and Acceleration of the Development of Antibody
Agonists
J.C. Hus, PhD, Senior Director, Informatics, Diagonal Therapeutics
The DIAGONAL platform, a cutting-edge integration of ML and physicsbased methodologies overcomes technical limitations that hindered agonist
antibody discovery in the past and allows for reproducible and reliable designof developable agonist antibodies against any multimeric receptor complex.
We will illustrate the method by presenting the four case studies where the
DIAGONAL platform helped us to design antibody agonists targeting four
structurally distinct receptor complexes with a 100% success rate.

9:05 A Compendium of Kinase Anti-Targets Associated with
Adverse Events Mined from Toxicity Data
Rayees Rahman, PhD, Co-Founder & CEO, Harmonic Discovery
Kinase inhibitors are a successful category of therapeutics used in treatinga wide variety of disease. Despite their efficacy, these drugs often present
clinically relevant adverse events that can limit their therapeutic utility. To
improve modeling of kinase inhibitor toxicity in patients, we extensively minedboth literature and publicly available toxicity data to develop the Kinase AntiTargets Compendium, a database of kinases statistically associated withspecific toxicities.

9:35 Networking Coffee Break
10:05 Foundation Models Require Significantly Less Bioactivity Data
to Discover Potent and Selective Ligands for a New Target
Jason Rolfe, PhD, Co-Founder & CTO, Variational AI
Generative AI foundation models trained on enormous datasets achieve
human-level performance in domains like natural language. A complementary
approach to small-molecule drug discovery is hampered because thehundreds of millions of available bioactivity measurements are noisy andinconsistently collected. We overcome these difficulties and construct a
small-molecule foundation model that yields high-accuracy predictions anddiscovers potent and selective ligands on targets with orders of magnitudeless bioactivity data.

10:35 Has Generative AI Had an Impact on Small Molecule Design?
Alba Macias, PhD, Director, Drug Design, Exscientia Inc.

46 | DiscoveryOnTarget.com

We present Exscientia’s approach to drug discovery and the importantrole of generative small molecule design in the process. The discovery of
a novel LSD1 inhibitor and a successful proof-of-concept study leading
to the discovery of novel, bispecific anti-malaria agents are presented as
applications of generative design.

11:05 Has AI/ML Significantly Impacted Drug Design & Optimization:
Discussion With Session Speakers
11:35 Predicting Bioactivity Before the Clinic
Henry Valle, Customer Support Specialist, CAS
The latest offering from CAS, the makers of CAS SciFinder, combines our highquality, comprehensive substance and chemistry data with the biological dataneeded to advance medicinal chemistry and drug discovery processes. In thissession, you’ll get a chance to preview the CAS BioFinder Discovery Platform,
including integrated predictive models, and learn about the future of the CAS
life sciences initiative.

12:05 pm Transition to Lunch
12:10 Luncheon Presentation (Sponsorship Opportunity Available) or
Enjoy Lunch on Your Own
12:40 Session BreakAI FOR RNA DRUG DISCOVERY
1:15 Chairperson’s Remarks
1:20 Combining NMR Transverse Relaxation Times (T2) andComputational Chemistry to Target RNA
Barak Akabayov, PhD, Professor, Department of Chemistry, Ben Gurion
University of the Negev
Using a unique combination of NMR and computational chemistry, we havedeveloped novel antibacterial small molecules by targeting an RNA hairpin
within the ribosomal PTC. The optimization models used a dataset of small
molecules, and their docking scores were crucial in establishing designprinciples for new small molecules with improved bioactivity. We synthesizedmolecules, tested their ability to inhibit the ribosome, and demonstrated thebinding mechanism to the RNA hairpin.

1:50 LightON mRNA: Anima’s mRNA Lightning Brings AI to mRNA
Biology
Generoso Ianniciello, Chief Business Officer, Anima Biotech
Using high-content, high-throughput imaging, we have generated over 2 billion
visualizations to train our mRNA image neural network to identify diseasesignatures. Our massively parallel automated mRNA lab tests thousands ofmolecules, identifying active ones that visually restore diseased cells to theirhealthy state. MOAi technology utilizes the mRNA knowledge graph, our LLM,
and the Lightning co-pilot, rapidly pinpointing mechanisms of action andmolecular targets, through a unified, scalable interface.

2:20 Presentation to be Announced
2:50 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

Cambridge Healthtech Institute’s 3rd Annual

AI/ML-Enabled Drug Discovery – Part 1
Leveraging GenAI to Improve Speed, Efficiency and Effectiveness
OCTOBER 1-2, 2024

IN-PERSON BREAKOUT: How to Quantify Biology to Inform AI/
ML-Driven Decisions in Drug Discovery
Arvind Rao, PhD, Associate Professor, Department of Computational
Medicine and Bioinformatics, University of Michigan
Yuan Wang, PhD, Head of Research Analytics, UCB Pharma

3:35 Grand Opening Refreshment Break in the Exhibit Hall with
Poster Viewing and Best of Show Voting Begins

AI MODELS HELPING TRANSLATIONAL RESEARCH
4:30 Chairperson’s Remarks
Yuan Wang, PhD, Head of Research Analytics, UCB Pharma

4:35 Computational Evaluation of Human-Relevant in vitro Disease
Models Enables Phenotype Differentiation
Yuan Wang, PhD, Head of Research Analytics, UCB Pharma
Early translational studies using human-relevant in vitro models can help ourunderstanding of disease pathobiology by simulating hallmark phenotypes inpatients. To study these phenotypes, we have developed both 2D and 3D invitro human models using iPSC-derived cardiomyocytes. We have analyzed
the behavior of these models using computational methods like signal
processing and computer vision. We will present promising results from thisanalysis as well as potential caveats.

5:05 Generative AI for Toxicology and Drug Safety
Weida Tong, PhD, Director, Division of Bioinformatics & Biostatistics, National
Center for Toxicological Research, US FDA
This presentation will showcase examples from FDA projects in GenerativeAI, focusing on its application using Generative Adversarial Networks (GANs)
in predictive toxicology, translational toxicology, and drug safety assessment.
Specifically, these projects apply GANs to: (1) Learn from existing animal
study data to generate animal study results without conducting actual
experiments; (2) Generate toxicogenomics data based solely on experimental
design; and (3) Translate findings from one organ to another.

5:35 AI Methods to Integrate Multi-modal Omics, Spatial and Single
Cell Profiling to Identify Gene Regulatory Programs
Arvind Rao, PhD, Associate Professor, Department of Computational Medicine
and Bioinformatics, University of Michigan
Spatial profiling technologies coupled with non-spatial profiling like scRNAseq
have the potential to enable a multi-factorial, multi-modal characterizationof the tissue microenvironment. Advances in statistics and ML can aid
interpretation and integration with companion data like bulk and singlecell
genomics. I will discuss analysis paradigms from machine learning that canbe used to integrate and then prioritize gene regulatory programs underlying
oncogenesis (as well as therapeutic candidates) using case studies.

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
7:05 Close of Day
WEDNESDAY, OCTOBER 2

7:30 am Registration Open and Morning Coffee
7:55 Chairperson’s Remarks
Woody Sherman, PhD, CIO, Psivant Therapeutics

We present a set of grand challenges for computational tools in small
molecule drug discovery. This unifying framework will enable thecommunity to more readily evaluate the effectiveness of computational
methods that have the potential to aid in the discovery of novel
therapeutics. Insights presented here stem from experts that span drug
hunters, method developers, and thought leaders in addition to lessons
learned from our internal drug discovery efforts.

9:00 Computationally Augmented Total Synthesis
Timothy Newhouse, PhD, Associate Professor, Department of Chemistry, Yale
University
Efficient syntheses of complex small molecules often involve speculative
experimental approaches. The challenge of such plans is that experimental
evaluation of high-risk strategies is resource intensive, as it entails iterative
attempts at unsuccessful strategies. This presentation describes acomplementary strategy that combines creative human-generated syntheticplans with robust computational prediction of synthetic feasibility. This work
defines how machine learning models can drive complex molecule synthesis.

9:30 Sponsored Presentation (Opportunity Available)
10:00 Coffee Break in the Exhibit Hall with Poster Viewing

PLENARY KEYNOTE PROGRAM
10:50 Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Close of AI/ML-Enabled Drug Discovery – Part 1
Conference

8:00 FEATURED PRESENTATION: Grand Challenges for
Computers in Drug Discovery
Woody Sherman, PhD, CIO, Psivant Therapeutics

DiscoveryOnTarget.com | 47

Cambridge Healthtech Institute’s 3rd Annual

AI/ML-Enabled Drug Discovery – Part 2
AI/ML for Identifying Novel Targets, Leads and Predicting Therapeutic Efficacy
OCTOBER 2-3, 2024

WEDNESDAY, OCTOBER 2

PLENARY KEYNOTE PROGRAM
10:50 am Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Enjoy Lunch on Your Own

AI/ML FOR PROPERTY PREDICTIONS
1:45 Welcome Remarks
1:50 Chairperson’s Remarks
Sean Ekins, PhD, Founder & CEO, Collaborations Pharmaceuticals, Inc.

1:55 Predicting Proteolysis-Targeting Chimeras’ (PROTACs) ADME/
Tox Properties
Sean Ekins, PhD, Founder & CEO, Collaborations Pharmaceuticals, Inc.
We have tested a small set of PROTACs against several human drugtransporters in vitro as well as in zebrafish for their effects on embryoand larval mortality, morphology, embryo photomotor response, andlarval photomotor response. We will report the preliminary outcomes ofthese combined assessments and discuss the implications for PROTACs
development as well as how this data could be used for machine learningmodel generation and evaluation.

2:25 Structure Prediction of Cyclic Peptides via Molecular Dynamics
and Machine Learning
Yu-Shan Lin, PhD, Associate Professor, Chemistry, Tufts University

48 | DiscoveryOnTarget.com

A major obstacle to cyclic peptide development is that little structural
information is available, as most cyclic peptides adopt multiple conformations
in solution. By combining molecular dynamics simulation and machinelearning, we can now provide simulation-quality cyclic peptide structure
predictions in seconds to enable structure-based design of cyclic peptides
and an understanding of their sequence–activity relationships.

2:55 Maximizing your return on computational drug
discovery with AI-powered serverless HPC
Fengbo Ren, Founder & CEO, Fovus Corp
Fovus is a groundbreaking serverless HPC platform designed to simplify
and optimize cloud HPC for enterprises. Utilizing AI-powered cloud HPC
strategy optimization and logistics orchestration, Fovus eliminates cloudcomplexities. It ensures and sustains time-cost optimality, making HPC
easily accessible and manageable for the digital R&D teams in Fortune 500
and high-tech startups/unicorns alike. Fovus recently empowered a biotech
startup to get drug discovery insights >100x faster while slashing the cloud
cost by 7x. Join this talk to learn how you get back lost productivity andspeed up drug discovery at reduced costs by leveraging Fovus.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 Data-Driven Optimization in Medicinal Chemistry
Barak Akabayov, PhD, Professor, Department of Chemistry, Ben Gurion
University of the Negev
Data-driven drug design relies on computational optimization andchemoinformatics to identify molecular features and predict bioactivity. This
involves collecting and preprocessing chemical datasets, identifying influential
features, and using selected features to optimize molecular structures andimprove bioactivity. By incorporating these steps in our process, we havegenerated new molecules with improved bioactivity for various targets,
outperforming traditional methods in terms of speed and precision.

4:45 DNA-Encoded Libraries for Machine Learning: Deep Data at
Scale
Patrick McEnaney, PhD, Senior Scientist, High Throughput Chemistry, insitro
To build better models of small molecule binders to target proteins, highquality training sets are essential. Leveraging DNA-encoded libraries (DELs)
with billions of molecules, we utilize our selection technology to generate datawith true negatives and accurately rank ordered true positive binders. We areworking to utilize these large-scale data sets to enhance the predictive powerof our small molecule protein binding models.

5:15 Dinner Short Course Registration**Premium Pricing or separate registration required. See Short Courses page fordetails.

5:15 Diversity Discussion (Sponsorship Opportunity Available)
IN-PERSON DISCUSSION: Fostering Diversity through Mentoring
Naytia Byrd, Manager, Human Resources, Ovid Therapeutics, Inc.
Saudat Fadeyi, PhD, MBA, Director, Business Development, Ovid
Therapeutics, Inc.
Fred Manby, DPhil, Co-Founder & CTO, Iambic Therapeutics
Joel Omage, Research Scientist II, CVM Disease Area, Novartis Institutes
for BioMedical Research, Inc.
Andrew Zhang, PhD, Director, Chemical Biology, AstraZeneca
Topics for discussion will include, but certainly not be limited to:• How to increase awareness and address hidden barriers and biases inlife sciences• How to motivate early-career scientists to seek out mentors andresources

Cambridge Healthtech Institute’s 3rd Annual

AI/ML-Enabled Drug Discovery – Part 2
AI/ML for Identifying Novel Targets, Leads and Predicting Therapeutic Efficacy
OCTOBER 2-3, 2024

• How to convince senior leadership to take time for coaching the next
generation of leaders and support DEI initiatives• How to create simple and impactful opportunities for mentors andmentees to connect and collaborate​​

6:00 Dinner Short Courses**Premium Pricing or separate registration required. See Short Courses page fordetails.

8:30 Close of Day
THURSDAY, OCTOBER 3

7:30 am Registration Open and Morning Coffee

INSIGHTS FROM VENTURE CAPITALISTS
8:00 PANEL DISCUSSION: Trends in Drug Discovery

Moderator: Daniel A. Erlanson, PhD, Chief Innovation Officer, Innovation
and Discovery, Frontier Medicines Corporation
Panelists:
Jernej Godec, PhD, Principal, Atlas Venture
Jenna Hebert, PhD, Senior Associate, RA Capital Management
Jamie Kasuboski, PhD, Partner, Luma Group
Jasmina Marjanovic, PhD, Partner, Takeda Ventures
Swetha Murali, PhD, Vice President, OMX Ventures

AI-ENABLED DECISION-MAKING
8:45 Chairperson’s Remarks
Shruthi Bharadwaj, PhD, Global Lead, Digital & Analytics, R&D Global
Operations, Sanofi

8:50 A Specialized Platform for Innovative Research Exploration(ASPIRE): Lowering the Barrier to Drug Development by Applying
Automation, Data Analytics, and AI/Machine Learning to Chemistry
and Biology
Sean Gardner, MS, Scientific Program Manager, Office of Special Initiatives,
NCATS, National Institutes of Health
The gap between drug discovery and information science continues toclose, hence there has never been a better time to leverage the power of AI/
ML techniques to advance our understanding of the relationships between
chemical and biological space. NCATS and the greater scientific community
have identified focus areas that need to be addressed and supported in order
to transform the design-synthesize-test cycle to transition to be more datadriven.

9:20 AI-Driven Hit Finding: A Perspective from the CACHE
Challenges
Matthieu Schapira, PhD, Principal Investigator, Structural Genomics
Consortium, Professor, Pharmacology & Toxicology, University of Toronto
CACHE is a series of prospective computational hit-finding challenges.
Results from the first challenges confirm that the field is in an exploratorymode, where a variety of ways to implement deep learning methodologies
are tested with mixed success. Fragment-based and de novo generative
design strategies are repeatedly among the best performing computational
workflows in the first challenge. Lessons from the second challenge will also
be presented.

9:50 FEATURED PRESENTATION: A Primer on Machine
Learning for Experimental Molecular Researchers – Principles,
Practicalities, and Pitfalls

Adrian Whitty, PhD, Associate Professor, Department of Chemistry,
Boston University
Lowering the barrier to entry to Machine Learning (ML), for scientists
without strong backgrounds in computer science and statistics, isimportant for broadening access to these powerful methods. I will
describe a set of methods we, as experimentalists, have found useful as
entry points to ML, with examples. The focus is on conceptualizing theunderlying principles, and on appreciating the key scientific decisions
and controls that lead to meaningful outcomes.

10:20 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT: How Successful Are AI/ML Approaches
in Drug Development Today?
Shruthi Bharadwaj, PhD, Global Lead, Digital & Analytics, R&D Global
Operations, Sanofi
Sean Gardner, MS, Scientific Program Manager, Office of Special
Initiatives, NCATS, National Institutes of HealthDmitri Kireev, PhD, Professor, Department of Chemistry, University ofMissouri

IN-PERSON BREAKOUT: Using AI/ML for Lead and Target
Discovery

Barak Akabayov, PhD, Professor, Department of Chemistry, Ben Gurion
University of the Negev
Diane M. Joseph-McCarthy, PhD, Professor of the Practice, Biomedical
Engineering, Boston University
Petrina Kamya, PhD, Global Head of AI Platforms, Vice President Insilico
Medicine; President, Insilico Medicine Canada, Insilico
Harpreet Saini, PhD, Senior Director, Informatics, Astex Pharmaceuticals
Ltd.

11:05 Coffee Break in the Exhibit Hall with Poster Viewing and Bestof Show Awards Announced

ACCELERATING DISCOVERY USING AI/ML STRATEGIES
11:45 AI at the Frontier: Pioneering Rare Disease Research andPatient Outcomes
Linxin Gu, MS, CEO, TechConnect
In the fight against rare diseases, AI technologies offer unprecedented
opportunities to accelerate discovery and enhance patient care. We utilize
AI to bridge significant gaps in rare disease research, focusing on improving
diagnostic accuracy, speeding up discovery, and tailoring treatments toindividual patient needs. Our approach leverages deep learning and genetic
algorithms to identify novel drug targets and predict therapeutic outcomes,
thus reducing time and cost bringing treatments to market.

12:15 pm Closed-Loop Discovery: Integrating AI, Data Science, andHuman Expertise
Jessen Yu, Senior Director, Data Science, Valo Health

DiscoveryOnTarget.com | 49

Cambridge Healthtech Institute’s 3rd Annual

AI/ML-Enabled Drug Discovery – Part 2
AI/ML for Identifying Novel Targets, Leads and Predicting Therapeutic Efficacy
OCTOBER 2-3, 2024

Our talk explores how data scientists, ML modelers, medicinal chemists,and others have collaborated to accelerate small molecule drug discovery
through our closed-loop discovery process. At its core, closed-loop discovery
is an integrated, streamlined pipeline that rapidly propagates information
through the design-make-test-analyze cycle. We’ll illustrate how each expert
contributes to the overarching goal and how we’ve tackled the challenge ofenabling effective collaboration among these diverse personas.

12:45 DEL-ML: BIG Data Leap in Early Stage Drug
Discovery
Mohamed Abouzleikha, VP & Head, X-Chem
DNA-encoded libraries (DELs) have transformed the landscape of early-stage
drug discovery, facilitating the identification of novel modulators targeting awide array of therapeutic protein targets. The vast amount of data generatedby DELs presents an exceptional opportunity for harnessing machine learningtechniques in hit identification within drug discovery. However, this leap
into big data landscape is accompanied by challenges such as data quality,
imbalanced datasets, and model evaluation. In this presentation, we explore
the current state of machine learning applications in DELs, shedding lighton challenges and proposing strategies to address them. Additionally, we
introduce ArtemisAI DEL implementation, a pipeline tailored specificallyfor processing DEL data, showcasing its efficacy across a comprehensive
array of targets. Within this overview, we aim to navigate the integration ofmachine learning in the field of DELs, guiding the way for groundbreaking
advancements in early-stage drug discovery.

3:35 Interaction-Based Hit Discovery Platform to Orphan Targets
Dmitri Kireev, PhD, Professor, Department of Chemistry, University of MissouriInteraction-based screening and design are promising novel strategies for
hit finding and lead optimization. The key information unit in the interaction
realm is a thin interface between the interacting ligand and protein. When fed
to deep neural networks, interaction signatures may infer SAR for unliganded
proteins by exploiting structural data across ligands and proteins. We give an
overview of the approach and describe its successful applications to several
challenging targets.

4:05 Assessment of Target Druggability Enabled by Machine
Learning
Diane M. Joseph-McCarthy, PhD, Professor of the Practice, Biomedical
Engineering, Boston University
Identification of hot spots on the surface of macromolecules is key toevaluating the druggability of novel targets and the likelihood of finding new
chemical entities. Computational hot-spot mapping was performed across a
set of drug targets, and a machine learning approach was employed to selectthe top druggable sites. Within this context, the utility of AI-generated protein
models obtained using AlphaFold, including ensembles of structural models,
was assessed.

4:35 Close of Conference

1:15 Transition to Lunch
1:20 LUNCHEON PRESENTATION: Talk Title to be
Announced
Michael Bellucci, Sr Dir of R&D, XtalPi Inc

1:50 Dessert Break in the Exhibit Hall with Last Chance for Poster
Viewing

AI-DRIVEN TARGET DISCOVERY
2:30 Chairperson’s Remarks
Harpreet Saini, PhD, Senior Director, Informatics, Astex Pharmaceuticals Ltd.

2:35 Integrative Computational Genetics Approach for Target
Discovery of ALS
Harpreet Saini, PhD, Senior Director, Informatics, Astex Pharmaceuticals Ltd.
We have developed a computational, genetics-based approach which
integrates functional data from GWAS, ontologies, and biological networks
to predict potential drug targets with evidence for disease association.
We obtained a list of target genes associated with ALS and prioritized
potential target genes by integrating structural information and cell-typetranscriptomics data.

3:05 FEATURED PRESENTATION: Target Discovery
Using AI—The Story behind Insilico Medicine’s
Discovery and Validation of MYT1 as a Target
Implicated in Breast Cancer

Petrina Kamya, PhD, Global Head of AI Platforms, Vice President Insilico
Medicine; President, Insilico Medicine Canada, Insilico
Using PandaOmics, we identified MYT1 as a promising new therapeutictarget for breast and gynecological cancer. PandaOmics is Insilico
Medicine’s AI-driven target discovery platform that leverages multi-modal
data to discover targets implicated in a disease. To further validate theselection of MYT1, we leveraged Chemistry42 to design and optimize alead compound that exhibits remarkable selectivity over WEE1 and has
promising in vivo antitumor efficacy.

DiscoveryOnTarget.com | 50

Cambridge Healthtech Institute’s 8th Annual

Physiologically Relevant Translational Models
3D Organoids and Other in vitro Models for Preclinical Drug Development and
IND Submissions | OCTOBER 1-2, 2024

TUESDAY, OCTOBER 1

7:00 am Registration Open and Morning Coffee

UNDERSTANDING TRANSLATIONAL CHALLENGES
7:55 Welcome Remarks
8:00 Chairperson’s Remarks
Madhu Lal Nag, PhD, CSO, InSphero

8:05 Perspectives and Opportunities Analysis of Translational in
vitro Models from the 3Rs Collaborative
Sally Thompson-Iritani, DVM, PhD, Assistant Vice Provost, Animal Care &Outreach & 3Rs, University of Washington
This presentation will include a comprehensive analysis of translational in
vitro models from the perspective of the 3Rs Collaborative. We will explore
current methodologies, challenges, and opportunities in developing andutilizing these models to enhance biomedical research while minimizing
animal use. It delves into the potential impact of these models for futureadvancements and collaboration in the pursuit of humane and effective
research practices.

8:35 Evidentiary Considerations to Build Confidence Including
Complex in vitro Models in a Weight-of-Evidence Approach to
Support Advancing New Therapies to Clinical Trials
Nicholas King, MS, Executive Director, Critical Path Institute
There is a significant opportunity for a paradigm shift in drug development
and discovery by integrating complex in vitro models (CIVM). Stakeholders
need to identify unmet needs and establish criteria for qualification andimplementation of CIVM. CIVMs may play an important role in a weight-ofevidence approach when utilizing human CIVMs to address questions when
animal models cannot.

9:35 Networking Coffee Break
10:05 FEATURED PRESENTATION: Advancing
Alternative Methods for Regulatory Use

Rodney L. Rouse, DVM, MBA, PhD, Deputy Director, Divisionof Applied Regulatory Science, Center for Drug Evaluation andResearch, United States Food and Drug Administration
This talk will attempt to convey FDA perspective on and interest in
developing and adopting alternative methods including review of FDA
involvement in efforts to advance alternative methods for regulatory use.

10:35 PANEL DISCUSSION: Navigating the Non-Animal Models
Ecosystem in Therapeutic Development

Moderator: Madhu Lal Nag, PhD, CSO, InSphero
Panelists:
Marc Ferrer, PhD, Director, 3D Tissue Bioprinting Laboratory, Divisionof Preclinical Innovation, National Center for Advancing Translational
Sciences, National Institutes of Health (NIH)
Nicholas King, MS, Executive Director, Critical Path InstituteRodney L. Rouse, DVM, MBA, PhD, Deputy Director, Division of Applied
Regulatory Science, Center for Drug Evaluation and Research, UnitedStates Food and Drug Administration
Sally Thompson-Iritani, DVM, PhD, Assistant Vice Provost, Animal Care &Outreach & 3Rs, University of Washington
Lindsay Tomlinson, PhD, Global Pathologist Resource Lead, Pfizer Inc.

11:35 Presentation to be Announced
12:05 pm Transition to Lunch
51 | DiscoveryOnTarget.com

12:10 Luncheon Presentation (Sponsorship Opportunity Available) or
Enjoy Lunch on Your Own
12:40 Session Break

EFFECTIVENESS OF IN VITRO MODELS
1:15 Chairperson’s Remarks
Marc Ferrer, PhD, Director, 3D Tissue Bioprinting Laboratory, Division of
Preclinical Innovation, National Center for Advancing Translational Sciences,
National Institutes of Health (NIH)

1:20 Characterization of a Human Colonic Microtissue as a Novel invitro Tool to Investigate Colonic Drug Disposition
Stephanie Kourula, PhD, Principal Scientist, Johnson & Johnson Innovative
Medicine
Human drug absorption is one of the critical parameters to define thebioavailability of drug candidates. Traditional in vitro models focus on
the small intestine where most drugs are absorbed. However, accurately
predicting colonic absorption has become increasingly relevant for drugs
targeting the colon to treat colonic diseases. Therefore, we have characterized
an organotypic 3D colon microtissue (EpiColon) as a novel in vitro platform tomodel colonic drug disposition.

1:50 FEATURED PRESENTATION: MicrophysiologicalModels of Chronic Inflammatory Diseases

Linda Griffith, PhD, Professor, Biological Engineering &Teaching Innovation, Massachusetts Institute of Technology
Can Microphysiological Systems (MPS) become true
replacements for animals in research and drug development? The
answer depends on the development of (relatively) low-cost, turnkey
technologies and bridging the gap between modern systems biology andthe MPS community. It requires conceptualizing human pathophysiology
through the lens of systems biology to design MPS that capture chronic
inflammatory diseases: immune components, organ-organ crosstalk, andsex dimorphism.

2:20 Human-on-a-Chip Systems for Therapeutic Evaluation andRegulation Submission for Neurological Diseases
James Hickman, PhD, Professor, NanoScience Technology Center, University ofCentral Florida
Human-on-a-chip systems for safety and efficacy—with up to 5 organs—have
demonstrated up to a 28-day evaluation of compounds. Embodiments are afunctional NMJ system for ALS, MG, CMT, and an LTP model for AD. Sanofi
has used efficacy data from our conduction velocity model for an IND for CIDP
that enabled a clinical trial (#NCT04658472), now in Phase III. Other INDs forphenotypic models have also been filed.

2:50 In-Person Breakouts
In-Person Breakouts are informal, moderated discussions, allowing
participants to exchange ideas and experiences and develop futurecollaborations around a focused topic. Each discussion will be led by afacilitator who keeps the discussion on track and the group engaged. To get
the most out of this format, please come prepared to share examples fromyour work, be a part of a collective, problem-solving session, and participate
in active idea sharing. Please visit the Breakouts page on the conference
website for a complete listing of topics and descriptions.

Cambridge Healthtech Institute’s 8th Annual

Physiologically Relevant Translational Models
3D Organoids and Other in vitro Models for Preclinical Drug Development and
IND Submissions | OCTOBER 1-2, 2024

IN-PERSON BREAKOUT: Standardization of Complex in vitro
Models (CIVMs) in Drug Development

Linda Griffith, PhD, Professor, Biological Engineering & Teaching
Innovation, Massachusetts Institute of Technology
James Hickman, PhD, Professor, NanoScience Technology Center,
University of Central Florida
Stephanie Kourula, PhD, Principal Scientist, Johnson & Johnson
Innovative Medicine
Lindsay Tomlinson, PhD, Global Pathologist Resource Lead, Pfizer Inc.

WEDNESDAY, OCTOBER 2

7:30 am Registration Open and Morning Coffee

DEVELOPING COMPLEX DISEASE MODELS
7:55 Chairperson’s Remarks
Claus Jorgensen, PhD, Team Leader, Systems Oncology, Institute of Cancer
Research

3:35 Grand Opening Refreshment Break in the Exhibit Hall with
Poster Viewing and Best of Show Voting Begins

8:00 Modeling Complex Interactions between Tumor and Host Using
Organoids

AI MODELS HELPING TRANSLATIONAL RESEARCH

Claus Jorgensen, PhD, Team Leader, Systems Oncology, Institute of Cancer
Research
Tumors are complex ecosystems where cancer cells are embedded within acomplex microenvironment comprising multiple infiltrating cell types and apathologically remodeled extracellular matrix. While much progress has been
made in establishing and interrogating epithelial and stem cell-like models,
incorporation of cells from the microenvironment and biophysical changes ischallenging. Here, I will describe our efforts to develop and interrogate models
of tumor cells and the conscripted microenvironment.

4:30 Chairperson’s Remarks
Yuan Wang, PhD, Head of Research Analytics, UCB Pharma

4:35 Computational Evaluation of Human-Relevant in vitro Disease
Models Enables Phenotype Differentiation
Yuan Wang, PhD, Head of Research Analytics, UCB Pharma
Early translational studies using human-relevant in vitro models can help ourunderstanding of disease pathobiology by simulating hallmark phenotypes inpatients. To study these phenotypes, we have developed both 2D and 3D invitro human models using iPSC-derived cardiomyocytes. We have analyzed
the behavior of these models using computational methods like signal
processing and computer vision. We will present promising results from thisanalysis as well as potential caveats.

5:05 Generative AI for Toxicology and Drug Safety
Weida Tong, PhD, Director, Division of Bioinformatics & Biostatistics, National
Center for Toxicological Research, US FDA
This presentation will showcase examples from FDA projects in GenerativeAI, focusing on its application using Generative Adversarial Networks (GANs)
in predictive toxicology, translational toxicology, and drug safety assessment.
Specifically, these projects apply GANs to: (1) Learn from existing animal
study data to generate animal study results without conducting actual
experiments; (2) Generate toxicogenomics data based solely on experimental
design; and (3) Translate findings from one organ to another.

5:35 AI Methods to Integrate Multi-modal Omics, Spatial and Single
Cell Profiling to Identify Gene Regulatory Programs
Arvind Rao, PhD, Associate Professor, Department of Computational Medicine
and Bioinformatics, University of Michigan
Spatial profiling technologies coupled with non-spatial profiling like scRNAseq
have the potential to enable a multi-factorial, multi-modal characterizationof the tissue microenvironment. Advances in statistics and ML can aid
interpretation and integration with companion data like bulk and singlecell
genomics. I will discuss analysis paradigms from machine learning that canbe used to integrate and then prioritize gene regulatory programs underlying
oncogenesis (as well as therapeutic candidates) using case studies.

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing

8:30 Functional Brain Region-Specific Neural 3D Cellular Models for
Drug Screening
Marc Ferrer, PhD, Director, 3D Tissue Bioprinting Laboratory, Division of
Preclinical Innovation, National Center for Advancing Translational Sciences,
National Institutes of Health (NIH)
There is a need for neural models that incorporate the physiologicalcomplexity of the brain and are compatible with high throughput screening
platforms. We have used iPSC-derived neural cells to make functional
brain region-specific neural 3D cellular models in multi well plate format for
drug screening. We will show data demonstrating neural spheroids withspontaneous and synchronized calcium oscillations and spatially definedneural circuit models produced using bioprinting techniques.

9:00 Monolayers, Organoids, and Multi-Cell Type Spheroids:
Patient-Derived Tumor Models for the Preclinical Assessment ofExperimental Therapeutics
Nathan P. Coussens, PhD, Scientific Director, Molecular Pharmacology
Laboratory, Frederick National Laboratory for Cancer Research
Translation throughout the discovery/development pipeline into the clinic
requires assays and model systems with physiological and pharmacologicalrelevance. The ability to incorporate patient-derived tumor cells into assays
with sufficient complexity to predict patient tumor responses could accelerate
the development of new therapies. This presentation will describe the useof various patient-derived tumor models from the National Cancer Institute’s
Patient-Derived Models Repository for the evaluation of approved andinvestigational anticancer agents.

9:30 Sponsored Presentation (Opportunity Available)
10:00 Coffee Break in the Exhibit Hall with Poster Viewing

7:05 Close of Day

DiscoveryOnTarget.com | 52

Cambridge Healthtech Institute’s 8th Annual

Physiologically Relevant Translational Models
3D Organoids and Other in vitro Models for Preclinical Drug Development and
IND Submissions | OCTOBER 1-2, 2024

PLENARY KEYNOTE PROGRAM
10:50 Plenary Keynote Chairperson’s Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech
Institute

10:55 PLENARY KEYNOTE: Discovery ofTransformative Rx to Treat Obesity and RelatedDiseases

Richard DiMarchi, PhD, Distinguished Professor of Chemistry
and Chair, Biomolecular Sciences, Indiana University; former Executive,
Lilly and Novo Research Labs
To address obesity, a medicinal challenge that warrants broad moleculardiversity, we pioneered the pharmacological strategy of recruiting
endogenous hormones to optimize physiological mechanisms. Our
discovery of single-molecule, multi-mechanism incretins enabled
breakthrough efficacy in lowering body weight. The integrated
pharmacology of these endocrine proteins and nuclear hormonesis providing a library of drug candidates that promises great clinicaloutcomes for obesity and associated diseases that have historically
been intractable.

11:40 PLENARY KEYNOTE: Fragment-Based Drug
Discovery for Elusive Cancer Targets

Stephen W. Fesik, PhD, Professor of Biochemistry,
Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer
Research, Vanderbilt University
The most highly validated cancer targets (KRAS, MYC, and WNT)
affecting the majority of cancers are thought to be impossible to drug.
Using fragment-based methods that I pioneered over 25 years ago,
we have discovered mutant selective and pan KRAS inhibitors, potent
inhibitors of the MYC cofactor WDR5, and degraders of b-catenin in
the WNT pathway. These novel inhibitors/degraders should have atremendous impact on cancer treatment in the future.

12:25 pm Close of Physiologically Relevant Translational Models
Conference

DiscoveryOnTarget.com | 53

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Conference Venue and Hotel:
Sheraton Boston
39 Dalton Street
Boston, MA 02199

Discounted Room Rate: $309 s/dDiscounted Room Rate Cut-off Date: September 2, 2024

For additional information please visit
DiscoveryOnTarget.com/Travel

Present a Poster and Save $50
Cambridge Healthtech Institute encourages attendees to gain further
exposure by presenting their work in the poster sessions. To secure
an onsite poster board and/or ensure your poster is included in theconference materials, your full submission must be received, and yourregistration paid in full by September 6, 2024.

Deadline: September 6, 2024

Reasons you should present your research poster at this conference:•Your research will be seen by our international delegation,
representing leaders from top pharmaceutical, biotech, academic andgovernment institutions•

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