bluuebunny/crossref_metadata_2025_split huggingface dataset:
KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Authors: Chutake Yogesh K. , Mayo Michele F. , Dumont Nancy , Filiatrault Jessica , Breitkopf Susanne B. , Cho Patricia , Chen Dapeng , Dixit Vaishali S. , Proctor William R. , Kuhn Eric W. , Bollinger Martinez Sarah , McDonald Alice A. , Qi Jianfeng , Hu Kan-Nian , Karnik Rahul , Growney Joseph D. , Sharma Kirti , Schalm Stefanie S. , Gollerkeri Ashwin M. , Mainolfi Nello , Williams Juliet A. , Weiss Matthew M. 
Published: December 2024

Abstract
Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors have demonstrated limited activity, underscoring an unmet need for a better approach to target MDM2. KT-253 is a highly potent and selective heterobifunctional degrader that overcomes the MDM2 feedback loop seen with small-molecule MDM2/p53 interaction inhibitors and induces apoptosis in a range of hematologic and solid tumor lines. A single intravenous dose of KT-253 triggered rapid apoptosis and sustained tumor regression in p53 wild-type acute myeloid leukemia and acute lymphoblastic leukemia xenograft models. Additionally, a single intravenous dose of KT-253 in combination with standard-of-care venetoclax overcame venetoclax resistance in an acute myeloid leukemia xenograft model. The data herein define the therapeutic potential of KT-253 and support its clinical development in a range of hematologic and solid p53 wild-type malignancies, as a monotherapy and in combination with standard-of-care agents.
Abstract A014: OICR41103: a chemical probe for investigating DCAF1 function and therapeutic potential
Authors: Noureldin Mahmoud , Kimani Serah , Wilson Brian , Halabelian Levon , Al-awar Rima 
Published: December 2024

Abstract
DCAF1 is a multifunctional protein that plays an important role in cellular processes, including protein degradation, cell cycle regulation, and immune function, by serving as a substrate receptor for RING-type CRL4 and the HECT family EDVP E3 ubiquitin ligases. Due to its involvement in various biological pathways and diseases, such as cancer and viral infections, there is a growing need for tools to study and regulate DCAF1 functions. Building upon our previous discovery of OICR-38268, a small-molecule binder of the DCAF1 WD40 domain, we have developed an improved chemical probe, OICR-41103. This compound exhibits enhanced binding affinity and selectivity for the WD40 domain of DCAF1. We successfully crystallized OICR-41103 with the WD40 domain, revealing its binding mode. Our probe binds to the WD40 domain of DCAF1 with a low nanomolar affinity in biophysical assays, and engages this domain in cells at nanomolar concentrations. This work presents a valuable chemical probe for studying DCAF1 function and provides a foundation for future drug discovery efforts, either by directly targeting DCAF1 or leveraging it for PROTAC-based strategies
Citation Format: Mahmoud Noureldin, Serah Kimani, Brian Wilson, Levon Halabelian, Rima Al-awar. OICR41103: a chemical probe for investigating DCAF1 function and therapeutic potential. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A014
Abstract A019: Discovery of a potent and brain-penetrable tubulin inhibitor SB-216 that shows efficacy in primary tumor growth and brain metastasis
Authors: Adeleye Kelli L. , Pochampally Satyanarayana , Krutilina Raisa , Wang Rui , Yue Junming , Seagroves Tiffany , Duane Miller D. , Li Wei 
Published: December 2024

Abstract
A major clinical challenge in cancer treatment is to prevent and treat metastatic disease. Despite the significant advancements in targeted therapy and immunotherapy, chemotherapeutic drugs, including taxanes, remain one of the mainline systemic treatment options for several major cancer types. However, the prolonged use of taxanes has been associated with the development of multidrug resistance, dose-limiting hematopoietic toxicity, and neurotoxicity, frequently presenting as persistent peripheral neuropathy. In addition, these drugs have limited blood-brain barrier penetration, and thus they are not effective in treating brain tumors or brain metastases from other cancer types, particularly breast cancer metastases. We have developed a new generation of tubulin inhibitors, termed colchicine binding site inhibitors (CBSIs). Unlike taxanes, these compounds bind to the colchicine site in tubulin, structurally less complex than taxanes which enables fine-tuning of physical-chemical properties, and shows the ability to overcome acquired drug resistance to existing taxane drugs. One of the best inhibitors in this class of compounds is SB-216. We have solved the high-resolution crystal structure of SB-216 in a complex with tubulin protein (PDB: 6X1F) and confirmed its mode of action. Extensive preclinical evaluations of SB-216 in a number of tumor models, including taxane-resistant prostate cancer, melanoma, ovarian cancer, and triple-negative breast cancer, indicated that SB-216 is highly potent in suppressing both primary tumor growth and tumor metastases. Importantly, SB-216 shows high brain penetration and shows efficacy in suppressing brain metastases from triple-negative breast cancer. SB-216 also has good drug-like properties and shows strong promise as a new generation of tubulin inhibitor for systemic cancer treatments, not only in brain metastasis from non-CNS tumors but also potentially be useful for brain tumors such as glioma. The work is supported by NIH/NCI grants R01CA14876 and R01CA276152 and the DoD grant HT9425-23-1-0216.
Citation Format: Kelli L. Adeleye, Satyanarayana Pochampally, Raisa Krutilina, Rui Wang, Junming Yue, Tiffany Seagroves, Duane D.Miller, Wei Li. Discovery of a potent and brain-penetrable tubulin inhibitor SB-216 that shows efficacy in primary tumor growth and brain metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A019.
Abstract A020: Liposomal topotecan with low-intensity focused ultrasound utilization to improve drug penetration with brain parenchyma in pediatric brain tumors
Authors: Mangoli Avani , Kim Sarah , Blethen Kathryn , Everhart Angela , Nikiforov Sasha , Grant Gerry , Avigliano Luke 
Published: December 2024

Abstract
The blood-brain barrier (BBB) remains a significant obstacle in delivering effective chemotherapeutics to treat pediatric brain tumors, limiting drug penetration and reducing therapeutic outcomes. To overcome this challenge, we investigated the use of liposomal topotecan (TPT), encapsulated in a sonosensitive formulation, designed for controlled release triggered by low-intensity focused ultrasound (LIFU). In this study, we evaluated the in vitro efficacy of a sonosensitive liposomal topotecan formulation. The liposomal topotecan was created using remote loading with an ammonium sulfate gradient. TPT was loaded at a drug-to-lipid ratio of 1:10. The liposome was composed of hydrogenated soy PC, cholesterol, and DSPE-PEG2000. IC50 assay comparing free topotecan to the liposomal topotecan indicated that the cytoxicity of free TPT is lower than liposomal TPT indicating a sustained release of drug which would decrease long term toxicity. In addition, pharmcokinetic fluorescent quantification of liposomal topotecan showed linear increase in free drug (ug/uL) as liposomal TPT concentration is increased in brain homogenates. We hypothesize that tumor growth inhibition and overall survival would be significantly improved in mice receiving LIFU-mediated liposomal topotecan delivery. Our future work includes additional pharmokinetics with survival analysis in vivo with and without low intensity focused ultrasound. These results highlight the potential of combining liposomal drug formulations with focused ultrasound to overcome the challenges of BBB permeability, offering a promising therapeutic strategy for improving drug accumulation and survival outcomes in pediatric brain tumor models.
Citation Format: Avani Mangoli, Sarah Kim, Kathryn Blethen, Angela Everhart, Sasha Nikiforov, Gerry Grant, Luke Avigliano. Liposomal topotecan with low-intensity focused ultrasound utilization to improve drug penetration with brain parenchyma in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A020.
Abstract IA003: Synthetic lethality: Pathways to therapeutic discovery
Authors: Durocher Daniel 
Published: December 2024

The orchestration of DNA repair is of fundamental importance to the maintenance of genomic integrity and tumor suppression. DNA damage must be detected in the context of the varied chromatin landscape, its presence must be communicated throughout the cell to alter many ongoing processes, and the machinery that will mend the lesion must be recruited to the damage site. In my presentation, I will discuss our recent efforts in mapping genome maintenance pathways using genome-scale CRISPR/Cas9 screens in human cells. I will highlight how these screens can be used to identify new genome stability factors, characterize drug responses and provide new insights into the genetic architecture of the genome stability network. I will finally present how these screens can also identify potentially actionable synthetic lethal genetic interactions that could form the basis of new oncology drug discovery efforts.
Citation Format: Daniel Durocher. Synthetic lethality: Pathways to therapeutic discovery. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA003
Abstract IA004: Overcoming traditional design limitations with AI-based discovery
Authors: Hallett David J. 
Published: December 2024

The properties of a new drug are set at the point of design, including any potential design flaws. Many small molecules that make it to human trials fail to progress beyond Phase 1 due to these flaws, which manifest as unacceptable side effects (either alone or in combination), meaning the drug (and therefore the pathway it is modulating) can never be adequately evaluated. This presentation will highlight how, through the thoughtful generation of a precise target candidate profile (TCP) and the subsequent use of GenAI, clinical candidates can now be precision designed to more exacting standards. Such molecules have the potential to have improved therapeutic indices, even against protein targets that are usually associated with mechanism-based adverse events.
Citation Format: David J. Hallett. Overcoming traditional design limitations with AI-based discovery. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA004
Abstract IA007: Preclinical Approaches to Discovery and Development of Novel Combination Therapies
Authors: Mettetal Jerome T. 
Published: December 2024

Drug combinations provide an important tool to address the complexity of tumor biology, and the ability to drive deeper and more durable responses has led to many successful combination regimens in clinical use today. There are more possible novel combination regimens than can be feasibly explored clinically, and preclinical studies have become a common tool to identify and prioritize combinations partners for clinical investigation. Historically, these approaches have focused heavily on identification of synergy, however, a growing body of research is beginning to indicate that synergy may not be a key predictor of clinical utility. To better understand the role of synergy in combinations, we experimentally explored acquired resistance to combination therapies in preclinical models, and counterintuitively, find that combinations which derive activity through synergy rather than additivity can lead to less undesirable outcomes. Specifically, we find that the combinations which rely on synergy are more likely to develop resistance as well as demonstrate greater loss of combination activity upon acquisition of resistance than an equally active additive combination. We propose that instead of relying on synergy for combinations discovery, that a framework based on the 5Rs can be employed which emphasizes a more holistic view of combination rationale, development, and proposed clinical utility. We demonstrate the application of these principles to discovery of novel therapeutic agents in analysis of a large-scale pan-tumor screen, and how these factors can be used to identify novel rational combination partners linked to specific disease segments which drive activity in vivo. As more agents with novel mechanisms enter clinical development, preclinical studies will play an increasingly important role in designing combination regimens which can attack the tumor from multiple angles, leading to better activity, and present a more favorable therapeutic index.
Citation Format: Jerome T. Mettetal Preclinical Approaches to Discovery and Development of Novel Combination Therapies. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA007
Abstract IA010: Bioengineering cell-based therapeutics
Authors: Veiseh Omid 
Published: December 2024

Abstract
Cell-based therapeutics are an emerging modality that can potentially treat many currently intractable diseases through uniquely powerful modes of action. Our group is innovating new biomaterials and cellular constructs for medicine and biology by combining chemical biology, cellular engineering, and multi-scale fabrication. We have pioneered innovative approaches to synthesizing and in vivo screening of large libraries of biomaterial formulations for tailored applications in immunology and medicine. In my talk, I will describe our advances in discovering immunomodulatory biomaterials that can interact appropriately with the host immune system for localized immunomodulation. I will highlight our efforts to develop “cytokine factories” locally activating the innate and adaptive immune response to generate systemic immunotherapy and eradicate metastatic cancer. This approach has advanced to phase I/II human clinical trials for treating recurrent, refractory ovarian cancer.
Citation Format: Omid Veiseh. Bioengineering cell-based therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA010.
Abstract IA017: Transferrin receptor targeting chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins in cancer
Authors: Zhou Xin 
Published: December 2024

Abstract
The membrane and extracellular proteome plays central roles in health and disease. Harnessing TfR1, a constitutive, rapidly internalizing receptor overexpressed in a broad spectrum of cancers, we developed Transferrin Receptor Targeting Chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins. In two applications, we show that TransTACs enabled the targeting of drug-resistant epidermal growth factor receptor (EGFR)-driven lung cancer and the reversible control of primary Chimeric Antigen Receptor (CAR)-T cells. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and for targeted cancer therapy.
Citation Format: Xin Zhou. Transferrin receptor targeting chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA017.
Abstract IA022: DYP688, a first-in-class PMEL17-targeted antibody drug conjugate delivering a Gq/11-specific inhibitor for the treatment of metastatic uveal melanoma
Authors: Wk Josephzore , D'Alessio Joseph A. , Yerramilli-Rao Padmaja , Blankenship John , Buntin Kathrin , Burger Matthew , Chen Zhuoliang , Cho Young Shin , Davis John , Ebel Nicolas , Eisfeld Jochen , Haberkorn Anne , Hainzl Dominik , Hoffmaster Keith , Napp Matthias , Pistorius Dominik , Rauniyar Vivek , Reynolds Aimee , Romanet Vincent , Schnell Christian , Seiss Katherine , Tschantz William R. , Wieland-Berghausen Susanne , Wimmer Laurin , Wuersch Kuno , Zhang Alan , Manchado Eusebio 
Published: December 2024

Abstract
Activating mutations in GNAQ/GNA11, encoding the G protein α subunits Gq and G11, are the most frequent genetic alterations in uveal melanoma (UVM) and considered to be critical for the initiation and maintenance of this malignancy. Despite inhibitors of Gq and G11 exhibiting promising preclinical anti-uveal melanoma activity, their therapeutic potential is limited by on-target toxicities associated with the ubiquitous expression and critical biological processes mediated by these G proteins. Here we report the discovery of a novel Gq/11 inhibitor-based antibody-drug-conjugate (ADC), DYP688, that selectively targets UVM cells, while sparing normal Gq/11-dependent cells. This conjugate consists of the highly potent and selective Gq/11 inhibitor SDZ475 (FR900359) conjugated to an antibody targeting PMEL17, a lineage gene having significant differential expression in melanoma. DYP688 potently inhibits Gq/11 oncogenic signaling, resulting in selective antiproliferative activity and apoptosis in PMEL17-positive, GNAQ/11-mutant UVM cells. In vivo, DYP688 exhibits marked and durable tumor regression in GNAQ/11-mutant UVM models, including patient-derived xenograft and liver metastasis models. Finally, we show that DYP688 features favorable preclinical pharmacokinetic and safety profiles, supportive of clinical evaluation. A phase 1 clinical trial with DYP688 is currently ongoing to assess the safety, tolerability and preliminary anti-tumor activity in patients with metastatic UVM and other GNAQ/11-mutant melanomas (clinicaltrials.gov identifier NCT05415072).
Citation Format: Josephzore Wk, Joseph A. D'Alessio, Padmaja Yerramilli-Rao, John Blankenship, Kathrin Buntin, Matthew Burger, Zhuoliang Chen, Young Shin Cho, John Davis, Nicolas Ebel, Jochen Eisfeld, Anne Haberkorn, Dominik Hainzl, Keith Hoffmaster, Matthias Napp, Dominik Pistorius, Vivek Rauniyar, Aimee Reynolds, Vincent Romanet, Christian Schnell, Katherine Seiss, William R. Tschantz, Susanne Wieland-Berghausen, Laurin Wimmer, Kuno Wuersch, Alan Zhang, Eusebio Manchado. DYP688, a first-in-class PMEL17-targeted antibody drug conjugate delivering a Gq/11-specific inhibitor for the treatment of metastatic uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA022.
Abstract PR002: EP300 loss of function is a pan-cancer sensitizer to BET inhibition
Authors: Babak Tomas , Truesdell Peter , Vontz Greg , Heinecke Peter , Villa Doris Coto , Dai Meiou 
Published: December 2024

Abstract
Genetically targeted therapies have proven to be a successful approach to treating cancer because they inhibit the causal (driver) biology of tumors that is absent in healthy cells. While targeted therapies exist for most oncogenes, only a small fraction of loss-of-function (LoF) tumor suppressor genes (TSGs) have been drugged to date, despite TSG mutations causing 2/3 of all cancer. Here we report a novel 1st-in-class genetically targeted opportunity using BET inhibitors to treat EP300 LoF cancers. Among the hundreds of pharmacogenetic screens that we have conducted, this interaction is similar to PARP-BRCA1/HRD in significance, and among the strongest we have discovered. It is cancer-type agnostic and holds up with all potent BET inhibitors in various pre-clinical models, including PDXs. Mechanistically, we demonstrate that apoptosis induced by DNA catastrophe arising from pre-mature entry into S phase plays a significant role. BET inhibition blocks timely assembly of DNA replication factors, which leads to G1 arrest in healthy cells; cancer cells that lack p300, a key regulator of CDK2, and CDK7, proceed through G1-S before replication deficiencies can be resolved. EP300 loss of function is a causal driver in more than 25,000 new cancer cases per year in the US and there currently are no genetically targeted options for these patients. This presentation will focus on the discovery, characterization, and clinical re-entry plan for our BET inhibitor LFB-190, to treat EP300 LoF solid tumors.
Citation Format: Tomas Babak, Peter Truesdell, Greg Vontz, Peter Heinecke, Doris Coto Villa, Meiou Dai. EP300 loss of function is a pan-cancer sensitizer to BET inhibition. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR002