Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — European Protein Degradation Congress 2021
20 slides from Monte Rosa Therapeutics's conference presentation, September 2021
Slide 1: From Serendipity to Rational Design
From Serendipity to Rational Design Taking Molecular Glue Degraders to New Heights Sept 2021 MONTE ROSA 4634 M / 45°56′12.6″N 07°52′01.4″E / SWITZERLAND Monte Rosa Therapeutics 1
Slide 2: Monte Rosa Therapeutics Overview
Monte Rosa Therapeutics Overview Taking molecular glue degraders (MGDs) to new heights Next-generation molecular glue-based targeted protein degradation platform developing breakthrough small molecule MGD drugs that selectively degrade therapeutically-relevant proteins Targeting the undruggable
Slide 3: Molecular Glue Degraders
Molecular Glue Degraders A powerful and differentiated approach to eradicate disease-causing proteins Neosubstrates - Undruggable target space Cereblon IKZF1 or IKZF3 Ubiquitin Favorable drug-like properties Ubiquitination Clinically validated Proteasome MGD - lenalidomide Systematic and selective E
Slide 4: QuEEN Discovery Platform: Transformational Approach to MGDs
QuEEN™ Discovery Platform: Transformational Approach to MGDs Building a unique portfolio of precision medicines addressing high unmet medical need Degron Encyclopedia Glueomics Toolbox Proprietary pipeline Degron identification using an AI-powered deep neural net • Highly selective MGDs for (DNN) de
Slide 5: One Vision Modules Connects Novel Degrons to Degraders
One Vision™ Modules Connects Novel Degrons to Degraders Modular AI algorithm suite maximizes external databases to discover targets and MGDs One Vision™ Degron Encyclopedia™ Inputs Integrated Degron Mining Sequences Topology BC Score Target X Target Y Target Z ~3,000 proteins Sequence Structures …CK
Slide 6: New Chemical Space: MGD Anatomy and Evolving MGD Library
New Chemical Space: MGD Anatomy and Evolving MGD Library Increasing novelty and structural diversity to match the target space Understanding Increasing the Core-Warhead Chemical Diversity MGD Anatomy 0.2 0.4 Tanimoto similarity Core Degron domain 0.6 Warhead Cereblon 0.8 binding domain Lenalidomide
Slide 7: Glueomics Toolbox - Biomolecular Sciences
Glueomics Toolbox - Biomolecular Sciences A suite of compound profiling assays to support platform and pipeline Quantitative Proteomics Target ID & Validation Proteome-wide Structure-Degradation quantitation Degron Discovery Relationship to Drive Chemistry Optimization Structural Biology Cellular Pr
Slide 8: In-house Capabilities Accelerate Prediction-to-Validation
In-house Capabilities Accelerate Prediction-to-Validation Matching target space to chemical space In-vitro Screens Results In-silico Screens EC50 Values in Biochemical Ternary Complex HTRF Assay 120 100 <10 nM 80 10-100 nM biochemical # Compounds 100-1000 nM 60 1000-10000 nM 40 20 NanoBiT 0 In-silic
Slide 9: Chemocentric exploration of MGD space
Chemocentric exploration of MGD space Exploring target space in a degron agnostic fashion through cellular assays HT Proteomics Cell Based Phenotypic Screens Biotin Unbiased cellular screens BirA e.g. reporter assays, synthetic lethality P value CRBN/ DDB1 MGD phenotypic models Cul4 Transcriptomics
Slide 10: Rhapsody, QuEEN's in silico MGD Engine
Rhapsody, QuEEN’s in silico MGD Engine in-silico screening identifies hits for evaluation and predictive models in silico MGD screen Compare GSPT1 in silico hits to lab Predictive models ROC curve Weak Neosubstrate 1.0 predictions Degron True calls (rate) High scoring predictions E3 ligase enriched
Slide 11: Monte Rosa Pipeline
Monte Rosa Pipeline Monte Rosa Therapeutics 11
Slide 12: Monte Rosa Pipeline
Monte Rosa Pipeline Rapidly advancing wholly owned MGD programs IND- Target / Program Indication(s) Discovery Phase 1 Enabling Lung Cancer GSPT1 (NSCLC, SCLC) Vignette NEK7 Inflammatory Diseases Rationally Ovarian Cancer, designing CDK2 Breast Cancer MGDs with T and B Cell Malignancies, highly selec
Slide 13: Selectivity of MGDs
Selectivity of MGDs Multiple Approaches to Achieve Desired Selectivity Selective screening hits from our MGD Library e.g., NEK7 for inflammatory disorders Medicinal chemistry optimization against known neosubstrates e.g., GSPT1 for MYC-driven cancers Medicinal chemistry optimization against other pr
Slide 14: NEK7: Hits Identified from MGD Library Screen
NEK7: Hits Identified from MGD Library Screen NEK7 is a key component of the NLRP3 inflammasome NEK7 contains a highly Library screen identifies NEK7-directed MGD activity defined degron multiple MGDs to NEK7 is cereblon-dependent Degron Ternary complex formation assay (HTRF) X-L-X-X-G-X-P CAL51 CAL
Slide 15: NEK7-directed MGDs are Selective for NEK7
NEK7-directed MGDs are Selective for NEK7 Selectivity confirmed biochemically and by proteomics profiling MGDs are biochemically selective MGDs promotes NEK7- MGDs promotes selective for NEK7 CRBN proximity degradation of NEK7 Single-point HTRF screen selectivity Target Z-score NEK7 21.9 HTRF Dose R
Slide 16: GSPT1: Optimization of Compounds for Selectivity
GSPT1: Optimization of Compounds for Selectivity GSPT1-directed MGD downregulates GSPT1, but not other known cereblon-neosubstrates Selectivity vs known GSPT1-directed MGD is highly selective cereblon-neosubstrates MRT-1577 (µM) p-value 0 0.3 3 30 GSPT1 IKZF1 wild-type IKZF3 SALL4 p-value CK1α GSPT1
Slide 17: CDKs Have Highly Similar ATP-binding Sites but Unique Degron Sequence
CDKs Have Highly Similar ATP-binding Sites but Unique Degron Sequence CDK2 biochemical hits are selective over CDK1, CDK4 and CDK9 Degron sequence is diverse amongst MGDs are biochemically selective for CDK family members CDK2 over other CDK family members Example: CDK2 and CDK4 structural similarit
Slide 18: Rationally Optimized CDK2-Directed MGDs are Selective Degraders
Rationally Optimized CDK2-Directed MGDs are Selective Degraders Demonstration of selective CDK2 degradation with MGD treated cells Rhapsody™ homology model enables rapid Rationally optimized MGDs selectively chemistry optimization degrade CDK2 CDK2 CDK2-degron MGD CRBN p-value Protein fold-change; (
Slide 19: Unlocking the Full Potential of Protein Degradation with MGDs
Unlocking the Full Potential of Protein Degradation with MGDs Quantitative and engineered elimination of proteins across a broad spectrum of diseases Target Space Oncology (Degron) Immunology Inflammation Metabolic disorders Neurodegeneration Genetic diseases E3 ligases Chemical Space Cereblon (MGD
Slide 20: Thank You
Thank You MONTE ROSA 4634 M / 45°56′12.6″N 07°52′01.4″E / SWITZERLAND Monte Rosa Therapeutics 20
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