Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — 2nd Ligase Targeting Drug Development Summit 2022
24 slides from Kymera Therapeutics's conference presentation, Apr 27, 2022
Slide 1: Drugging Tissue Restricted E3 Ligases for TPD-based Precision Medicine
Drugging Tissue Restricted E3 Ligases for TPD-based Precision Medicine Hakryul Jo, Ph.D. Director, Platform Biology INVENTING NEW MEDICINES WITH TARGETED PROTEIN DEGRADATION April 27th, 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
Outline How We Select Therapeutic Targets • Drugging all target classes with multiple E3 ligases • Opportunities for tissue sparing E3 ligases How We Select Tissue Sparing E3 Ligases • Selection criteria for tissue restricted E3 ligases • A novel E3 ligase with broad utility for solid tumors ©2022 K
Slide 4: How We Select Our Targets
How We Select Our Targets Expanding the Druggable Proteome with TPD Undrugged Targets Clinically Validated Targets ID Clear Drugged Targets with Degrader Advantage UD UD No other technology can drug TR TR Unlocked by E3 Ligase Small molecule binders exist but Differential Expression unable to drug t
Slide 5: Unlocking a Clinically Validated Target by a Tissue Sparing E3
Unlocking a Clinically Validated Target by a Tissue Sparing E3 In Cancer Cell • Kymera has Kymera’s degrader characterized an E3 E3 Ligase is Almost using this E3 ligase ligase that is degrades target in expressed broadly Absent in One cancer cells but NOT in ONE Blood Cell Type blood cell type Bloo
Slide 6: New Opportunities for Clinically Validated Targets
New Opportunities for Clinically Validated Targets Ubiquitously Expressed Protein Targets WithWith required required or well- or well- With intolerable tolerated tolerated systemic systemic systemic pharmacology pharmacology pharmacology Ubiquitously Ubiquitously expressed expressed E3 ligases E3 li
Slide 7: Outline
Outline How We Select Therapeutic Targets • Drugging all target classes with multiple E3 ligases • Opportunities for tissue sparing E3 ligases How We Select Tissue Sparing E3 Ligases • Selection criteria for tissue restricted E3 ligases • A novel E3 ligase with broad utility for solid tumors ©2022 K
Slide 8: How We Select Tissue Sparing E3 Ligases
How We Select Tissue Sparing E3 Ligases L.E.D Criteria Serve to Identify Matching E3 Ligases Well- High POS Multiple hit established tox for TPD finding efforts profiles L application Clinically Tissue Next Gen Validated Targets E Sparing E3 Ligases Degrader Medicine D Ligandability; Expression; Deg
Slide 9: Desired Outcome for Tissue Sparing E3 Ligases
Desired Outcome for Tissue Sparing E3 Ligases E Increase of Therapeutic Index E3 Ligase Expression Target Degradation Expected Outcome Ubiquitous No Disease sparing Disease • Dose limiting toxicity tissues tissues • Limited clinical benefit Target Expression Restricted Complete Ubiquitous Disease (C
Slide 10: Example: Protein Expression of Select E3s in Healthy Tissues
E Example: Protein Expression of Select E3s in Healthy Tissues 32 Different Healthy tissues 5 Primary Tox Cell Models CRBN Ligase A Ligase B Ligase C Ligase D Ligase E Ligase F Ligase G Blood Gastrointestinal Reproductive Others Cell #1 Cell #2 Cell #3 Cell #4 Cell #5 • Complete absence across diffe
Slide 11: Example: Limited Utility for Highly Restricted E3 Ligases
E Example: Limited Utility for Highly Restricted E3 Ligases Ubiquitous Tissue Restricted Detection Rate (%) Log10(Concentration Estimate [nM]) Log10(Concentration Estimate [nM]) Log10(Concentration Estimate [nM]) 4 4 4 CRBN Ligase E Ligase F 100 2 2 2 75 50 0 0 0 25 -2 -2 -2 0 Data: Selected dataset
Slide 12: What Makes an E3 Ligandable and Druggable at Kymera?
L What Makes an E3 Ligandable and Druggable at Kymera? Site A Site B • Ligandability: likelihood Ligandable; MORE Druggable Ligandable; LESS Druggable of identifying a small- molecule binder with Ub Ub affinity < 1 uM Sub Sub A Ub B Ub • Druggability: likelihood E3 E2 E3 E2 of converting the ligand
Slide 13: Ligandability Assessment by Pilot Screens
L Ligandability Assessment by Pilot Screens Fragment-Based Cysteine Covalent Screen Screening Example of FBS by X-ray Crystal Covalent Screen by Intact MS x108 Criteria 3.5 Criteria • Availability of high 3 • Surface exposed quality protein with 2.5 Unlabeled reactive cysteines 2 Degrader robust cry
Slide 14: Why We Validate Degradative Activity of E3 Ligases
D Why We Validate Degradative Activity of E3 Ligases Different Types of Ubiquitin Linkages Unknown Risks for Novel E3 Ligases • >600 known E3 ligases in human • Not all E3 ligases are suitable for TPD application Ubiquitin: K63 M1 Ub Ub Ub Ub K63 M1 Ub Ub Ub K48 Ub K11 Ub Ub K48 Ub K11 Ub K63 Ub M1
Slide 15: How We Validate Degradative Activity of E3 Ligases
How We Validate Degradative Activity of E3 Ligases D New Proximity Assay Based on High Affinity Peptide-protein Pair Leveraging Peptide-Protein Pair Forced E3-Sub Interaction PoC of New Proximity System Example with Ligase D New Sub Degradation - + - + - + Dox P1 Ub E3-T1 High Affinity New Sub Sub#1
Slide 16: Outline
Outline How We Select Therapeutic Targets • Drugging all target classes with multiple E3 ligases • Opportunities for tissue sparing E3 ligases How We Select Tissue Sparing E3 Ligases • Selection criteria for tissue restricted E3 ligases • A novel E3 ligase with broad utility for solid tumors ©2022 K
Slide 17: A Novel Tissue Sparing E3 Ligase with Broad Cancer Utility
A Novel Tissue Sparing E3 Ligase with Broad Cancer Utility High Level Background Tractability Assessment Progress on Chemical Matter Ligase Type: RING domain-based Precedence and Datamining An example of Known Multiple degradative ✓ ❑ Contains ligandable ligand-bound Ligase D domains/protein family
Slide 18: Protein Expression of Ligase D in Healthy and Cancer Tissues
E Protein Expression of Ligase D in Healthy and Cancer Tissues 32 Different Healthy Tissues 5 Primary Tox Cell Models CRBN Ligase D Blood Gastrointestinal Reproductive Others Cell #1 Cell #2 Cell #3 Cell #4 Cell #5 CRBN Ligase D Log10(Concentration Estimate [nM]) Log10(Concentration Estimate [nM]) 4
Slide 19: Ligase D is Not Expressed in Blood Lineage Progenitors
E Ligase D is Not Expressed in Blood Lineage Progenitors Cereblon VHL Ligase D CD34+ Cells from 15 Donors Thyroid 40 Mesothelioma 30 Log2(Median TPM) Lung 6 Ligase D is detected Tumor 4 Liver at extremely low TPM 20 levels compared to 2 Head & Neck Cereblon and VHL Glioblastoma 10 Glioma Tox CD34+ C
Slide 20: Robust Degradation Toward Natural and Neo-substrates
D Robust “D” Toward Natural and Neo-substrates Degradation of Endogenous Substrate Degradation of Neo Substrates Empty Vector Ligase D Dox-inducible Stable Lines PoC of New Proximity System Varying Sub Amount - + - + - + Dox - + - + - + Dox E3-T1 Full length Sub Sub#1-P1 Internal del Sub C-term del
Slide 21: Validation of Druggability of Novel Site
L Validation of Druggability of Novel Site Identification of Covalent Ligands Validation of Functional Competency Functionalized Validation of Single Labeling Screen by E3 x108 Intact MS Workflow for covalent 3.5 3 ligands screen 2.5 Unlabeled Degrader Ligase D 2 labeled Retest & 1.5 Selectivity 1 5
Slide 22: Developing Next Gen Degrader for Precision Medicine
Developing Next Gen Degrader for Precision Medicine High POS Identified Well-established for TPD Multiple BM tox profiles L application Ligase D Ligands Degrader Clinically Sparing for Validated Targets E BM CD34+ Precision Cells Medicine D Work in Ligandability; Expression; Degradation Progress ©20
Slide 23: Summary and Future Ambition
Summary and Future Ambition Enabling TPD-based Precision Medicine • TPD with tissue sparing E3 ligases can help maximize the therapeutic index of clinically well-validated targets by minimizing on-target toxicity • Tissue restricted degradation can enable new therapeutic opportunities for these clas
Slide 24: Thank You
Thank You July 2021 ©2022 KYMERA THERAPEUTICS, INC. PAGE 24
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