Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — 4th Annual Targeted Protein Degradation Summit 2021
20 slides from Monte Rosa Therapeutics's conference presentation, Oct 27, 2021
Slide 1: Molecular Glue Degraders: From Serendipity to Rational Design
Molecular Glue Degraders: From Serendipity to Rational Design 4th Annual TPD Summit - October 27, 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 (MGDs)
Molecular Glue Degraders (MGDs) A powerful and differentiated approach to eradicate disease-causing proteins Undruggable target space Neosubstrates - Cereblon IKZF1 or IKZF3 Ubiquitin Favorable drug-like properties Ubiquitination Clinically validated Proteasome MGD - lenalidomide Systematic and sele
Slide 4: Cereblon (CRBN), the G-loop Degron and Beyond
Cereblon (CRBN), the G-loop Degron and Beyond A rational approach to unleash the full potential of MGDs PLATFORM BUILD PLATFORM PLATFORM AND VALIDATION EXPANSION DIVERSIFICATION Target G-loop degron MGD Cereblon (CRBN) Unraveling the Beyond the Beyond G-loop Degrome G-loop Degrome Cereblon EXPANDING
Slide 5: QuEEN Discovery Platform: A Transformational Approach to MGDs
QuEEN™ Discovery Platform: A Transformational Approach to MGDs Building a unique portfolio of precision medicines addressing high unmet medical needs Degron Encyclopedia Glueomics™ Toolbox Proprietary Library degron Specialized suite of in vitro and in silico Rationally designed, diverse Degron disc
Slide 6: The Degron Encyclopedia
The Degron Encyclopedia A rich, differentiated target space across protein domains and diseases Integrated Degron Mining Degron Encyclopedia >3000 predicted degron-containing proteins Sequence Broad disease landscape Top protein classes Deep Neural Net Genetic disease Catalytic activity Transcripti
Slide 7: Expanding the Target Space by Identifying More Degrons
Expanding the Target Space by Identifying More Degrons Example of degron-containing proteins in different diseases Immunology/ Neurology Genetic Diseases Cancer I-O Inflammation Kinase Demethylase Phosphatase DNA binding DNA binding Inflammation Solid tumors T-cell exhaustion ALS Blood DNA binding G
Slide 8: Expanding the Target Space by Identifying More Degrons
Expanding the Target Space by Identifying More Degrons Additional structural loops revealed beyond the G-loop degrome G-loop Architecture X-loop Protein Analysis Gly Lys Arg Asn Amino acid Gln at position 5 Ser Glu (top 10) Asp Pos 5 His Degron Leu 0 1000 2000 3000 4000 CRBN No. of Proteins X-loop d
Slide 9: 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 MGD Anatomy Increasing the Core-Warhead Chemical Diversity 0.2 0.4 Tanimoto similarity Core Degron domain 0.6 Warhead Cereblon 0.8 binding domain Lenalidomide 1 Scaffold evo
Slide 10: Glueomics Toolbox Accelerates Identification of MGDs
Glueomics™ Toolbox Accelerates Identification of MGDs Matching target space to chemical space In vitro Screens Results In-silico Screens EC50 Values in a Biochemical Ternary Complex HTRF Assay MGD Neosubstrate 120 <10 nM 100 10-100 nM 80 100-1000 nM biochemical # Compounds 1000-10000 nM 60 40 20 E3
Slide 11: Glueomics Toolbox Accelerates Exploration of MGD Space
Glueomics™ Toolbox Accelerates Exploration of MGD Space Exploring target space through chemoproteomics Proteomics Target Space Turbo-ID data for 15 representative MGDs Cell lines p-value A B C Protein fold-change; (log2) 0 25 50 75 G-loop X-loop Turbo-ID proximity ligation labels Unbiased discovery
Slide 12: Chemoproteomics Accelerates Prediction-to-Validation
Chemoproteomics Accelerates Prediction-to-Validation Experimental validation of targets using MS proximity (TurboID) and degradation assays TURBO-ID DEGRADATION Transcription Factor A TF A TF A p-value p-value Sickle cell disease Protein fold-change; (log2) Protein fold-change; (log2) Degron Novel p
Slide 13: Multiple Protein Domains Contain Degrons
Multiple Protein Domains Contain Degrons Degron-containing Protein Domains VAV1-directed MGDs Target the SH3 Domain Vav1-SH3 Rhapsody™ domain model C2H2 zinc finger Protein kinase WD40 repeats CRBN Cadherin repeats degron RNA recognition motif EGF-like HTRF Dose Response Immunoglobulin 15000 Src hom
Slide 14: Many Kinases Contain Degrons
Many Kinases Contain Degrons An opportunity to selectively degrade tough-to-selectively inhibit proteins Kinases with degrons Degrome TK (23%) TKL (14%) • Over 170 human kinases have predicted degrons STE (65%) • Degrons occur in kinase, SH3 and other domains • Includes multiple kinases with scaffol
Slide 15: Many Kinases Contain Degrons
Many Kinases Contain Degrons An opportunity to selectively degrade tough-to-selectively inhibit proteins > 30 Kinases identified from Turbo-ID TURBO-ID DEGRADATION NEK7 TK (23%) TKL (14%) NEK7 STE (65%) p-value p-value CMGC (38%) Protein fold-change; (log2) Protein fold-change; (log2) CK1 (42%) TURB
Slide 16: Many Kinases Contain Degrons
Many Kinases Contain Degrons An opportunity to selectively degrade tough-to-selectively inhibit proteins Degron sequence is diverse amongst CDK family members TK (23%) TKL (14%) Example: CDK2 and CDK4 structural similarity STE (65%) G-loop Degron N-lobe CMGC (38%) ATP-binding pocket CK1 (42%) C-lobe
Slide 17: CDK2-Directed MGDs are Selective over other CDKs
CDK2-Directed MGDs are Selective over other CDKs MGDs identified through biochemical screens induce cellular proximity with CRBN MGDs are biochemically selective over CDK1, MGDs promote CDK2-cereblon proximity and CDK4 and CDK9 are selective over other CDKs CDK1 | Cyclin A2 CDK2 | Cyclin E1 CDK2 EC5
Slide 18: Rationally Designed CDK2-Directed MGDs are Selective Degraders
Rationally Designed CDK2-Directed MGDs are Selective Degraders Demonstration of selective CDK2 degradation with MGD treated cells Rhapsody™ model enables rapid Rationally designed MGDs promote Rationally designed MGDs selectively chemistry optimization more selective CRBN proximity degrade CDK2 CDK2
Slide 19: Monte Rosa Pipeline
Monte Rosa Pipeline Rapidly advancing wholly owned MGD programs Target / Program Indication(s) Discovery IND-Enabling Lung Cancer GSPT1 (NSCLC, SCLC) NEK7 Inflammatory Diseases Ovarian Cancer, CDK2 Breast Cancer T and B Cell Malignancies, VAV1 Autoimmune Disease BCL11A SCD, β-Thalassemia Undisclosed
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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