Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — 2nd Annual TPD Europe Summit (March 2022)
19 slides from Monte Rosa Therapeutics's conference presentation, Mar 17, 2022
Slide 1: From Serendipity to Rational Design
From Serendipity to Rational Design Taking Molecular Glue Degraders to New Heights | 2nd Annual TPD Europe Summit, March 17, 2022 Amine Sadok, PhD Sr Director - Head of Discovery Technologies
Slide 2: Forward-Looking Statements
Forward-Looking Statements These materials include express and implied “forward-looking statements,” including forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward looking statements include all statements that are not historical facts, and i
Slide 3: Molecular Glue Degraders (MGDs)
Molecular Glue Degraders (MGDs) Expanding target space, fostering a new generation of drugs INHIBITOR PROTAC MGDs E3 Ligase E3 Ligase DRUGGABLE TARGETS UNDRUGGABLE TARGETS DRUGGABLE TARGETS Drugging Redrugging Drugging the Druggable the Druggable the Undruggable Target Space Expanding the Degradable
Slide 4: Our Rational Approach to Unleash the Full Potential of MGDs
Our Rational Approach to Unleash the Full Potential of MGDs Unraveling the Beyond the Beyond cereblon canonical degrome canonical degrome Neosubstrates - Cereblon Eg. IKZF1 MGD Eg. Lenalidomide Chemical Space Target Space Expanding the Degradable Proteome 4
Slide 5: QuEEN Discovery Platform: A Target-Centric Approach to MGDs
QuEEN™ Discovery Platform: A Target-Centric Approach to MGDs Degron encyclopedia Proprietary MGD library GlueomicsTM toolbox Degron discovery Rationally designed, diverse Specialized suite of in vitro and in using proprietary and growing library engaging a silico assays to discover, optimize and AI-
Slide 6: Expanding MGD Exit Vectorology Engages Novel Degron Classes
Expanding MGD Exit Vectorology Engages Novel Degron Classes MGD diversification Expanded MGD diversity engages more degron classes Degron: Class A Side- Class B chains Class C PPI domain 400+ Scaffolds 6 tSNE from structural fingerprints
Slide 7: MGDs Reprogram the Cereblon Surface
MGDs Reprogram the Cereblon Surface Remodeled MGD-CRBN surface enables selective engagement of neosubstrates Multiple points of contact for dialing in MGDs are rationally designed to exploit key contacts selectivity and potency to selectively engage different neosubstrates MGD MGD MGD MGDs reshape t
Slide 8: Glueomics Toolbox Accelerates Identification of MGDs
Glueomics™ Toolbox Accelerates Identification of MGDs Multiple assays enable rapid identification and validation of MGDs for novel targets in vitro screens Chemoproteomics - proximity Proteome-wide expression p-value Biochemical Protein fold-change; (log2) TMT Proteomics to evaluate: p-value • Prote
Slide 9: A Rich, Differentiated Target Space Across Protein Domains and Diseases
A Rich, Differentiated Target Space Across Protein Domains and Diseases Degron Encyclopedia >3000 proteins containing a predicted loop degron Degron-containing domains Predicted degrons Broad disease landscape C2H2 zinc finger Genetic disease Protein kinase Nervous system WD40 repeats Musculoskeleta
Slide 10: Degron Encyclopedia Predicts Degrons in Specific Kinases
Degron Encyclopedia Predicts Degrons in Specific Kinases 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 m
Slide 11: Degron Encyclopedia Predicts Degrons in Specific Kinases
Degron Encyclopedia Predicts Degrons in Specific Kinases Chemoproteomics confirm neosubstrate induced proximity and degradation > 30 kinases identified from Turbo-ID Turbo-ID Degradation KINASE A KINASE A KINASE B TK (23%) TKL (14%) KINASE B p-value p-value STE (65%) CMGC (38%) Protein fold-change;
Slide 12: Degron Encyclopedia Predicts NEK7 has Unique Degron
Degron Encyclopedia Predicts NEK7 has Unique Degron An opportunity to selectively degrade tough-to-selectively inhibit proteins NEK7 degron sequence is unique among NEK family TK (23%) TKL (14%) STE (65%) N-lobe ATP-binding CMGC (38%) pocket CK1 (42%) C-lobe Other (33%) AGC (33%) High sequence con
Slide 13: NEK7 as a Target for Inflammatory Disease
NEK7 (NIMA-Related Kinase 7) as a Target for Inflammatory Disease NEK7 is an essential regulator of the inflammasome NLRP3 Active NLRP3 inflammasome NEK7 Therapeutic hypothesis: Diseases with over-activated or ASC mutated NLRP3 inflammasome • NEK7 licenses NLRP3 assembly in a kinase independent Pro-
Slide 14: Rationally Designed NEK7-Directed MGDs are Selective
Rationally Designed NEK7-Directed MGDs are Selective Rhapsody model enables rapid Rationally designed MGDs NEK7-directed MGD promotes chemistry optimization promote selective CRBN proximity selective degradation of NEK7 NEK7 MGD Degron p-value p-value CRBN in vitro data Protein fold-change; (log2) P
Slide 15: NEK7-directed MGDs Modulate NLRP3 Pathway in Human Macrophages
NEK7-directed MGDs Modulate NLRP3 Pathway in Human Macrophages MGDs promotes NEK7 degradation NEK7-directed MGD compared and pathway engagement in hMDMs to NLRP3 inhibitor IL-18 150 LPS + Nigericin MGD (nM) + (Normalized to vehicle) LPS + Nigericin MGD Inzomelid %IL-18 level 100 (Normalized to Vehic
Slide 16: NEK7-directed MGD is CRBN-dependent and Requires Degron
16 %IL1β release %Caspase 1 activity (Normalized to Vehicle) (Normalized to Vehicle) U 0 100 120 20 40 60 80 nt N 0 100 120 140 20 40 60 80 re U oc at nt el ed re ls a N LP D t ed ig S M er SO Ve icin hi Ve LPS cl e hi cl 0. 64 0. e 64 3. 2 3. 2 16 16 80 80 40 40 0 2 0 MGD (nM) + LPS + Nigericin 20
Slide 17: Overactivation of the NLRP3 Inflammasome in Diseases
Overactivation of the NLRP3 Inflammasome in Diseases NLRP3 activating mutations Over-activated NLRP3 inflammasome Heart Myocardial infarction Lung Diabetic cardiomyopathy Asthma ARDS NLRP3 Metabolism Liver LRR Obesity Type II Diabetes Liver fibrosis C-terminal NEK7 Artherosclerosis Liver damage Pro-
Slide 18: Monte Rosa Pipeline
Monte Rosa Pipeline Rapidly advancing wholly owned MGD programs targeting undruggable proteins Next Target / Program Indication(s) Discovery IND-Enabling Clinical Anticipated Milestones Ownership NSCLC, SCLC and other GSPT1 IND filing mid-2022 MYC-driven Malignancies NEK7 Inflammatory Diseases IND-E
Slide 19: Thank You
~ Mp. Monte Rosa Therapeutics
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