Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — 2nd Ligase Targeting Drug Development Summit 2022
20 slides from Kymera Therapeutics's conference presentation, Apr 26, 2022
Slide 1: Chemically Harnessing Novel E3 Ligase Biology for Next-generation TPD Therapeutics
Chemically Harnessing Novel E3 Ligase Biology for Next-generation TPD Therapeutics Lewis D. Pennington, Ph.D. Senior Director, Head of Platform Chemistry INVENTING NEW MEDICINES WITH TARGETED PROTEIN DEGRADATION April 26th, 2022
Slide 2: Forward-looking Statements
Forward-looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 (PSLRA) and other federal securities laws. These statements include information about our current and future prospects and our operations and fi
Slide 3: Outline of Presentation
Outline of Presentation • Kymera’s pipeline and platform Founded • Identifying a small molecule 2016 ligand for a novel E3 ligase • Developing a heterobifunctional degrader for a POC POI* Recognition • Evaluating pharmacology for cellular POC efforts • Summary and Outlook Partnerships * POC, proof-o
Slide 4: Kymera's Pipeline of Novel Protein Degraders
Kymera’s Pipeline of Novel Protein Degraders Pathway Program Indication(s) Discovery IND Enabling Phase 1 Phases 2/3 Next Milestone Rights* Multiple Immuno- Patients POB KT-474 inflammatory Diseases: mid-22 IRAK4 HS, AD, RA Multiple molecules staged as others potential back ups if needed IL-1R/TLR I
Slide 5: We Want to Drug All Target Classes
We Want to Drug All Target Classes Expanding the Druggable Proteome with TPD Inadequately Drugged Clinically Validated Targets Undrugged Targets ID Targets with Clear UD No other technology can drug TR Enabled by E3 Ligase Tissue Degrader Advantage Restricted Expression Small molecule binders exist
Slide 6: Platform for Harnessing Novel E3 Ligase Biology
Platform for Harnessing Novel E3 Ligase Biology E3 Ligase Whole-body Atlas • RNA & protein expression profiles of ~ 600 E3s • Disease & healthy tissues & cells (tissue distribution, absolute abundance, & subcellular localization) • Novel E3 & POI pairing based on expression & biology Proprietary Che
Slide 7: Comprehensive Hit Finding Toolbox
Comprehensive Hit Finding Toolbox Cysteine Virtual Fragment- DEL Covalent HTS ASMS Screen Based Screen Screening Criteria Criteria Criteria Criteria Criteria Criteria • Availability of • High quality protein • Availability of high • Proteins have • Available high- • Availability of high- structure o
Slide 8: Guiding Principles
Guiding Principles Value-added Portfolio • Strategic pairing of novel E3s & POIs for targeted diseases • Judicious balancing of biology & chemistry risks Qualified Biology • Holistic assessment of novel E3s (“LED” qualification) • LED: ligandability, expression profile, & degradative activity Enable
Slide 9: Kymera‒GSK Partnership
Kymera‒GSK Partnership E3 Ligase DEL Selection Expertise Expertise* >80 1 E3s E3 DEL Selection Ligand Degrader Degrader Cell Discussed E3 Selection Qualification Optimization Generation POC Evaluated Today * DEL, DNA-encoded library ©2022 KYMERA THERAPEUTICS, INC. PAGE 9
Slide 10: Novel E3 Ligase X (E3LX): Value Proposition
Novel E3 Ligase X (E3LX): Value Proposition Current E3 Ligases are Limited E3LX Expression Profile by RNA-Seq# • All are ubiquitous: cereblon, VHL, MDM2, Healthy Tissues IAP, etc. VHL CRBN • Each has chemistry, biology, or safety E3LX challenges Improved Ubiquitous E3s Needed Primary Tumors VHL • No
Slide 11: E3LX Expression Profile Substantiated by Proteomics
E3LX Expression Profile Substantiated by Proteomics E3 Ligase Whole-body Atlas E3LX Protein Expression Profile Tissues HEALTHY Tissues** CRBN Ubiquitous E3LX E3 Ligases Restrictive CANCER Cell Lines*** Selective E3LX CRBN Targets ** Wang et al., Mol Syst Biol 2019, reprocessed and supplemented with
Slide 12: E3LX: Qualified Biology
E3LX: Qualified Biology E3LX Degradative Activity Expression Profile by AdPROM# • RNA & protein show favorable healthy & disease profile A549 Cells Stably Expressing GFP‒STK33 Fusion Protein for tissue-selective degradation; cytosolic & nuclear localization of protein E3LX Construct 1 E3LX Construct
Slide 13: E3LX: Enabled Chemistry
E3LX: Enabled Chemistry Hit Finding Strategy E3LX‒Ligand X Complex Structure by X-ray Crystallography (3.3 Å) • Binding sites unknown at time of DEL selection • DEL selection done at GSK (~ 100 unique DELs) • Diverse, 2‒4 cycle library; billions of compounds Carboxylate group Methylamino group X-ray
Slide 14: Ligand X: Key Properties
Ligand X: Key Properties Improved Properties Needed Molecular, Physicochemical, & Pharmacological Properties E3LX, Ligand X CRBN, Pomalidomide VHL, VH032 Binding affinity, Kd (mM) 0.20 1.2 0.60 Molecular weight, MW (Da) 623 273 473 Topological polar surface area, TPSA (Å2) 128 110 111 Lipophilicity,
Slide 15: Ligand X: Exploratory Binding SAR
Ligand X: Exploratory Binding SAR Carboxylic Acid is Important Binding Affinity Ligand X Analogue 1 Analogue 2 E3LX SPR Kd (mM) 0.20 9.5 46 DNA Exit Vector is Favorable Binding Affinity Analogue 3 Analogue 4 E3LX SPR Kd (mM) 0.16 0.14 ©2022 KYMERA THERAPEUTICS, INC. PAGE 15
Slide 16: Degrader X: Exploratory Binding SAR
Degrader X: Exploratory Binding SAR Degraders Have Lower Affinity Binding Affinity Degrader X (R = H) and Analogue 1 (R = Me) E3LX SPR Kd (mM) Degrader X = 1.6; Analogue 1 = 6.3 Methylene Linker Similar to Amine Binding Affinity Analogue 2 E3LX SPR Kd (mM) 0.89 ©2022 KYMERA THERAPEUTICS, INC. PAGE 1
Slide 17: Degrader X: Exploratory Cell-free Assays Toward Rapidly Assessing Inducible Degradative Activity
Degrader X: Exploratory Cell-free Assays Toward Rapidly Assessing Inducible Degradative Activity Ternary Complex Formation Cell-free Ubiquitination by AlphaLISA by Western Blot (WB)* MZ-1 Degrader X Degrader (mM) 1 20 10 1 BRD2-Ubn BRD2 (88 kDa) BRD4-Ubn BRD4 (152 kDa) * Cell lysate derived from OCI
Slide 18: Degrader X Analogue: Exploratory Cell-based Assays
Degrader X Analogue: Exploratory Cell-based Assays Toward Rapidly Assessing Inducible Degradative Activity Cell-based Degradation Cell-based Degradation Cell-based Degradation by WB by HiBiT Rescue Degrader X Analogue Concentrations Degrader X Analogue at 10 mM E3LX Wild-type E3LX Knock-out Degrader
Slide 19: Summary and Outlook
Summary and Outlook • E3LX: favorable tissue-selective expression profile was identified by the E3 ligase whole-body atlas at Kymera • The first SM ligand for E3LX, Ligand X, was identified by DEL selection at GSK • The first E3LX‒Ligand X complex structure by X-ray solved at Kymera • The first E3LX
Slide 20: Thank You Q&A
THANK YOU KYMERA
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