SGR-1505 is a potent MALT1 protease inhibitor with a potential best-in-class profile
Wu Yin, Min Ye, Netonia Marshall, Joanne BL Tan, Evan Paull, Zhe Nie, Michael Trzoss, Goran Krilov, Shulu Feng, Robert Pelletier, Jeff Bell, Paul Devine, Peter Skrdla, David Calkins, Mary Grimes, D. Hamish Wright, Karen Akinsanya
Schrödinger, Inc., 1540 Broadway, New York, NY 10036•Constitutive activation of the NF-κB signaling pathway is a molecular hallmarkof activated B cell like diffuse large B cell lymphoma (ABC-DLBCL), andmutations that trigger constitutive MALT1 protease activity (such as on CD79and CARD11) cause malignant B cell signaling in multiple B-cell malignancies.

MALT1 Biochemical Assay

240

IC50, nM

1,353

5,357

IC90, nM 

5015



JN

J-6s 28 d 633
RSG dayays28



Protease
Function

Substratecleavage

MALT1
SYKBTKIκBαBCL10CARD11

ScaﬀoldFunction

NF-κBNF-kB and Related Pathway Genes

IKK
complex

SGR-1505

Activation
Proliferation
Survival

Ex Vivo Whole Blood Assayfrom Healthy subjects(SGR-1505-102 Study)Inhibition of cytokine release from ex
vivo stimulation of human whole bloodcollected from healthy volunteers thatwere dosed with SGR-1505

EC50, nM

EC90, nM

843 - 1744

2,438 - 5,580

A

Schematics of RNAseq study. SGR-1505 or JNJ-6633 were
dosed for 28 days in OCI-LY3 model. Tumor samples
were collected 2hr post dosing on day 28 and analyzed
for RNA-seq.

B

NF-κB

Assay

SGR-1505 with venetoclax shows stronger combination effectcompared to JNJ-6633 in DLBCL cell line
Inhibition (%)

Cell-based assay

SGR-1505

SGR-1505In vitro
combination ofJNJ-6633 andvenetoclax inOCI-LY3 cells
following thetreatment for
4 daysIC50, nM

IC90, nM

MALT1 Biochemical Assay

1.3

773

485

BCL10 Cleavage Assay in OCI-LY10 Cells

2263

98

334

IL10 Secretion Assay in OCI-LY10 Cells

36

211

267

2,816

Antiproliferative Assay in OCI-LY10 Cells

71

181

430

5,670

NF-kB Reporter Assay in Jurkat Cells

37

113

242

4,122

JNJ-6633

Biochemical assay

IC90, nM

Venetoclax    

Percentage of S phase of OCI-LY3 cells treated withSGR-1505 and JNJ-6633 for 72 hours

Results•When tested in combination with venetoclax, SGR-1505 showed stronger
combination effect compared to JNJ-6633.

•Using RNA-seq analysis, SGR-1505 showed greater modulation of
NF-kB and related pathway genes compared to JNJ-6633. Changes ingenes related to cell cycle pathways, such as cell cycle, DNA damage,and apoptosis were identified and exclusively associated with SGR-1505
treatment. Consistent with the gene expression analysis, SGR-1505
treatment induced G1 arrest effect in DLBCL cell line at much lower doses
compared to JNJ-6633.

Conclusions•SGR-1505, a MALT1 protease small molecule inhibitor, consistentlydemonstrated stronger potency and better combinability withvenetoclax when compared to the clinical-stage JNJ-6633 compoundand greater effects on NF-kB and related pathway gene expression.

•A Phase 1 clinical trial in patients with mature B cell neoplasms
is currently ongoing (NCT05544019). The data presented heresuggests SGR-1505 has a potential best-in-class profile and supports
advancing the ongoing clinical development of SGR-1505.

SGR-1505

B550
1RSG cuteAw

Acute

Bliss synergy score

JNJ-6633

IC50, nM

In vitro
combination ofSGR-1505 andvenetoclax inOCI-LY3 cells
following thetreatment for 4days; (left) matrixof % of inhibitionin the CTG assay;(right) Blisssynergy score
calculated bysynergyfinderConsistent with the in vitro T-cell activation assay, SGR-1505 led to similarchanges in cytokine production in an ex vivo assay in the whole bloodcollected from our ongoing healthy volunteer clinical trial (the SGR-1505102 study).

SGR-1505 exclusively regulates cell cycle related pathway
genes in in vivo DLBCL CDX model

BJNJ-6633

Assay

Inhibition (%)

•Heatmap of Log2 Fold Change (LFC), of differentiallyexpressed genes in the Biocarta NF-kB pathway are
shown, with JNJ-6633 (left) in comparison to SGR-1505(right). Mean LFC across all genes is + 0.45 in SGR-1505
vs +0.37 in JNJ-6633.

B. Combination of JNJ-6633 and venetoclax

SGR-1505 showed excellent potency in the biochemical assay
and strong anti-proliferative effects on ABC-DLBCL cell lines
SGR-1505

Venetoclax

C

Bliss synergy score

VenetoclaxSGR-1505 showed excellent potency in the biochemical and cell based
assays compared to JNJ-6633. Results from an in vitro human primary
T-cell activation assay measuring cytokine production from whole bloodcollected from healthy donors suggested SGR-1505 is least ten-fold morepotent than JNJ-6633.

AHere we further characterized SGR-1505, in a series of in vitro and ex vivo
assays, as well as RNA-seq analysis to examine changes in gene expression
from in vivo tumor samples. We also compared SGR-1505 with a competitor
Phase I candidate, JNJ-67856633 (JNJ-6633).3,4

•

AA. Combination of SGR-1505 and venetoclax

Volcano plot of differential expressed genes between
SGR-1505 (left) and JNJ-6633 (right). -Log10 p-values areshown on the y axis, with Log2 fold change on the x axis;
genes with < 1e-4 p-values are highlighted in blue, > 2
absolute value Log2 change in green, and genes meeting
both criteria are in red. Selected outliers are annotated.

BackgroundPreviously, we described the discovery of novel MALT1 inhibitors with
anti-proliferative effects in non-Hodgkin B-cell lymphoma cells and the strong
anti-tumor activity of our MALT1 inhibitors across multiple tumor models aswell as combination potential with agents including standard-of-care.1,2
SGR-1505 is an oral potent small molecule allosteric inhibitor of MALT1 thatinhibits MALT1 enzymatic activity and demonstrates anti-proliferative activity
in ABC-DLBCL cell lines, both BTKi-sensitive (OCI-LY10) and BTKi-resistant(OCI-LY3). When administered as a single agent and in combination withthe approved Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, SGR-1505
demonstrated tumorostatic and regressive antitumor activity in ABC-DLBCL
cell line-derived xenograft and patient-derived xenograft models. These datasuggest that SGR-1505-mediated MALT1 inhibition has therapeutic potential forpatients with selected B-cell lymphomas.

Flow based cell analysis of OCI-LY3 cells treatedwith SGR-1505 for 72 hours demonstrated morepotent S phase inhibition, as compared to JNJ6633. Grey, G1 phase; Blue, S phase; and Black,G2/M phaseC    

RNA SeqB

Whole Blood was collected from healthy subjects dosed with oral SGR-1505
tablets and stimulated with anti-CD3/CD28. Cytokine was measured using
MesoScale Diagnostics (MSD) after 20hr of incubation.

Nucleus

B-CellReceptor(BCR)  78,096

 

SGR-1505 showed potent inhibition of cytokines ex vivo inthe whole blood collected from the SGR-1505-102 healthy
volunteer studyMALT1Inhibitor


IC90, nM

JNJ-6633



IC50, nM

SGR-1505


AssayJNJ-6633

B


SGR-1505  A

A

Following antigen-receptor stimulation and the activation of CBM complex,
MALT1 triggers NF-kB signaling and lymphocyte activation. MALT1 targets
key proteins in a negative feedback loop mediating termination of the NF-κB
response: a) as a scaffolding protein to activate the Inhibitor of IκB Kinase(IKK) complex and b) as a protease to inactivate negative regulators such as
RelB and A20.

Whole blood was collected from 3 healthy donors,
stimulated with anti-CD3/CD28, and titrated withincreased concentration of either SGR-1505 or JNJ6633. Cytokine was measured using MesoScale
Diagnostics (MSD) after 20hr of incubation.

SGR-1505 induces G1 arrest in DLBCL cells




•

MALT1 is one of the key regulators of physiological antigen receptor signallingin B cells and T cells, and is the only component of the CARMA1-BCL10-MALT1(CBM) signalosome which has proteolytic activity.

SGR-1505 shows stronger regulation of NF-kB and related
pathway genes than JNJ-6633 in in vivo DLBCL CDX model •SGR-1505 is at least ten-fold more potent than JNJ-6633
in a      
human primary T cell-based assay  

MALT1 is a paracaspase involved in NF-kB signaling

Venetoclax

RNA Seq at 2, 6. 12,
24h after treatment

APathway enrichment heatmap of cell-cycle
related pathways, across multi-time point studyof SGR-1505 and JNJ-6633 from the chronic
efficacy studies in OCI-LY3 model. Intensity ofcolor represents mean expression values acrosspathway genes (positive fold change: red;
negative: blue).

References
BPathway enrichment heatmap showing the mean
Log2 Fold Change of all genes in cell cycle related
pathways from an acute SGR-1505 study in OCILY3 model. Tumor samples were collected after
a single dose of SGR-1505 treatment at 2, 6, 12,
and 24hr. The largest increase across pathways
is observed at the 6h timepoint, followed bycontinued positive activity at 12 and 24h.

1. Characterization of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies.
Blood. Volume 138, Supplement 1, 23 November 2021, Page 1187
2. Identification of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies. Blood.
Volume 136, Supplement 1, 5 November 2020, Page 30
3. Phase 1 Study of JNJ-67856633, a first-in-human highly selective MALT1 inhibitor, in relapsed/refractory (R/R) B-cell non-hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia(CLL). EHA Library. Kalac M. 06/08/2023; 386453; P624
4. Phase 1 study of JNJ-67856633, a first-in-human MALT1 inhibitor, in relapsed/refractory (R/R)
B-cell non-hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL). HematologicalOncology Volume 41: 17th International Conference on Malignant Lymphoma, Palazzo dei
Congressi, Lugano, Switzerland, 13–17 June, 2023, Pages 131–132