Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — Technical Presentation (May 2022)
26 slides from Kymera Therapeutics's technical presentation, May 2022
Slide 1: Non-Clinical Safety Considerations when Developing Targeted Protein Degraders
Non-Clinical Safety Considerations when Developing Targeted Protein Degraders W i l l i a m P r o c t o r, P h D , D A B T Sen i or Di rector – Precl i n i cal Safety INVENTING NEW MEDICINES WITH TARGETED PROTEIN DEGRADATION May 2022
Slide 2: Proteome Editing is the New Frontier of Medicine
Proteome Editing is the New Frontier of Medicine Genome Proteome Essentially static Changes based on internal (genetic) and external Encodes (epigenetic) events Alterations are Alterations are responsible responsible for some for all diseases diseases Editing is irreversible Editing is reversible ©2
Slide 3: Proteome Editing with Targeted Protein Degradation
Proteome Editing with Targeted Protein Degradation A Nobel Prize (2004) Inspired Technology Targeted Small Disease-causing Molecule Expanded Opportunities 1 Target Protein 2 Protein Degraders • Small molecule binds to E3 and target protein to affect its degradation Degrader • Small Molecule only nee
Slide 4: Expanding the Druggable Proteome with TPD
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 but unable to drug target fully On
Slide 5: Common Approaches For Designing TPDs
Common Approaches For Designing TPDs Heterobifunctional Molecular Degraders Glues IMiDs (e.g.Thalidomide) POI E3 Ligase linker Ligand Binder • SM molecules w/ ligand for POI, linker region, • SMs that bind to natural protein-protein and ligand for E3 ligase interaction sites between a POI and E3 lig
Slide 6: Mechanism of Action Requires Efficient Ternary Complex Formation
Mechanism of Action Requires Efficient Ternary Complex Formation Minimal / no Optimal ternary Hook Effect complex complex = formation optimal degradation Hook-Effect - predominance of binary complexes Degrader A: DC50~10nM Degrader B: DC50>1000nM Quantitation of Ternary Complex by AlphaLISA • Effici
Slide 7: Heterobifunctional Degraders
Heterobifunctional Degraders
Slide 8: Heterobifunctional Degraders Often Exist in Unique Chemical Space
Heterobifunctional Degraders Often Exist in Unique Chemical Space • High MW / lipophilicity can lead to challenges for oral absorption • Non-specific binding of compounds to plastic/labware is possible • Intrinsic solubility can be limiting for both in vitro and TPDs in vivo studies • In vitro scree
Slide 9: In Vitro Study Considerations that Can Impact Data Interpretation
In Vitro Study Considerations that Can Impact Data Interpretation • Conventional approach: sequential sampling Cmpd A in PBS buffer 1.000 Half-life = 12 mins Area Ratio (test cpd/IS) Time points: aliquots 0 min Chemical 10 min 0.100 instability? Cmpd A (1 µM) 20 min in PBS Buffer 30 min 1 hr 0.010 I
Slide 10: Nominal and Measured IC50 Values – Impact on Screening Data
Nominal and Measured IC50 Values – Impact on Screening Data vs. Definitive In Vitro Studies Nominal IC50: 5 μM Measured IC50: 1 μM 0.01 0.1 1 10 0.01 0.1 1 • Need for determining / estimating in vitro solubility and nonspecific binding/adsorption • Impacts are broad and can affect 2ndary pharmacolog
Slide 11: High Tissue Partitioning Can be Observed with Heterobifunctional Degraders
High Tissue Partitioning Can be Observed with Heterobifunctional Degraders • High tissue to plasma ratios can be observed • Important to context relevance in relation free- drug levels (e.g., Kp,u,u) • Can be beneficial for PD/activity, prolonged terminal T1/2, ... Tissue to Plasma (T/P) ratios for
Slide 12: Factors that Determine Relevance of Preclinical Species for TPD Safety Assessment
Factors that Determine Relevance of Preclinical Species for TPD Safety Assessment 1. Exposure 2. Target Expression 3. Pharmacology 4. Metabolism Select species where the POI & E3 ligase are expressed in the same cells / tissues / Complete target degradation Metabolite coverage in Select species that
Slide 13: In Vitro Cross-Species Reactivity / Pharmacology Assessments
In Vitro Cross-Species Reactivity / Pharmacology Assessments • Overall Goal: Complete target degradation (>90%) in at least one non-clinical species and exposure multiples above that in general toxicology studies • In practice: need to identify species early on (e.g., during early lead-optimization
Slide 14: Example: Significant Cross-Species Potency Shifts Between Lead-like Molecules
Example: Significant Cross-Species Potency Shifts Between Lead-like Molecules • Efficient ternary complex formation required for pharmacologic activity (e.g., degradation) • Subtle changes across species with POI and/or E3 ligase structures/homology may lead to significant impacts on formation of te
Slide 15: Importance of Assessing Supra-Pharmacologic Doses Can Impact Species Selection
Importance of Assessing Supra-Pharmacologic Doses (> In Vivo DC90) Can Impact Species Selection Species Cross-Reactivity – In Vivo Dog NHP Target X %Degradation Target X %Degradation 59% 35% 7% Control 5mpk Target degradation was assessed in PBMCs isolated from animals treated with for 7d TPD 2 at v
Slide 16: Off-Target Assessment for TPD
Off-Target Assessment for TPD
Slide 17: Advantage of Heterobifunctional TPD is the High Degree of Selectivity
Advantage of Heterobifunctional TPD is the High Degree of Selectivity that Can Be Achieved IRAK4 Degrader STAT3 Degrader • Global proteomic approaches offer 3 unbiased view into on- and off- target pharmacology of TPD 2.5 • Compounds assessed for off-target 2 Pvalue (–log 10) effects at 10x DC90/95
Slide 18: What degree of Off-Target Proteome Coverage is Necessary for Safety Assessment of TPD?
What degree of Off-Target Proteome Coverage is Necessary for Safety Assessment of TPD? • There is a need to comprehensively assess off-targets of TPD due to catalytic nature, potency, and drivers for reversibility of off-target effects (e.g., protein re-synthesis) • Departure from traditional SM app
Slide 19: Time-Dependent Effects on Off-Target Profiling
Time-Dependent Effects on Off-Target Profiling: Elucidating Off-targets from Downstream Biology 2hr 4hr 8hr 24hr . . . . . . . . . . . . . . . . Volcano plots of global proteomic changes at various incubation timepoints from cell line X with an example TPD at 10x DC90 c oncentrations. Blue dot repre
Slide 20: E3 Ligase Selection and Aspects to Consider for Safety Assessment
E3 Ligase Selection and Aspects to Consider for Safety Assessment
Slide 21: IMiDs and Mechanism of Teratogenicity
IMiDs and Mechanism of Teratogenicity • Cereblon modulation determined to be responsible for thalidomide-mediated teratogenicity (Ito T. et al. Science. 2010 Mar 12;327(5971):1345-50). • Degradation of SALL4 via IMiD-CRBN leads to teratogenicity (Matyskiela ME, et al. Nat Chem Biol. 2018 Oct;14(10):
Slide 22: Proprietary Cereblon-Binder Containing TPDs Do Not Degrade SALL4
Proprietary Cereblon-Binder Containing TPDs Do Not Degrade SALL4 or other IMiD Neosubstrates 18 IMiD substrates Cereblon Cereblon Cereblon covered Binder Binder Binder iPSC’s Cereblon DMSO TPD 1 TPD 2 TPD 3 Pom. Binder SALL4 Actin Log2(Fold-Change vs. DMSO) -1 7 additional IMiD substrates assayed in
Slide 23: Novel E3 Ligases to Drug a New Generation of Targets
Novel E3 Ligases to Drug a New Generation of Targets TR Clinically Validated Targets Unlocked by E3 Ligase Differential Expression On target unwanted pharmacology limits clinical application • Focused on determining the expression profiles of ~600 unique E3 ligases • Patterns mapped in both disease
Slide 24: Overall Conclusions and Future Directions
Overall Conclusions and Future Directors • TPD offer unprecedented ability to selectively edit the proteome to impact human health and transform healthcare • This emerging modality requires special considerations when addressing exaggerated pharmacology, species selection, off-target profiling, and
Slide 25: Acknowledgments
Acknowledgments: Brad Enerson Vaishali Dixit Kan-Nian Hu Dapeng Chen Guowen Liu Frank Qi Haojing Rong Veronica Campbell Matt Weiss Susanne Breitkopf Kevin Scott Yi Zhang Chris De Savi Madison Adams The rest of the Kymera team
Slide 26: Questions
QUESTIONS
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