C4 Therapeutics, Inc. · NASDAQ:CCCC

C4 Therapeutics — 4th Targeted Protein Degradation Summit 2021

29 slides from C4 Therapeutics's conference presentation, October 2021

  1. Slide 1: Discovery of a Potent and Selective BRD9 BiDAC Degrader in Synovial Sarcoma

    Discovery of a Potent and Selective BRD9 BiDAC Degrader with Activity in a Preclinical Model of Synovial Sarcoma Kate Jackson 4th Targeted Protein Degradation Summit October 26-28, 2021 1

  2. Slide 2: Forward-looking Statements and Intellectual Property

    Forward-looking Statements and Intellectual Property Forward-looking Statements The following presentation contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,”

  3. Slide 3: BRD9: Drugging the Undruggable with a BiDAC Degrader Approach

    BRD9: Drugging the Undruggable with a BiDAC Degrader Approach Strong Rationale Clear Unmet Defined Patient for Degrader Approach Need Population Synovial sarcoma (SS) is Very limited benefit of US incidence: ~900 dependent on BRD9 due treatments for metastatic cases/year or advanced synovial to the

  4. Slide 4: Synovial Sarcoma is Driven by Aberrant BAF Complex Biology

    Synovial Sarcoma is Driven by Aberrant BAF Complex Biology cBAF BCL7 ncBAF BCL7 pBAF BCL7 PBRM1 Actin A/B/C Actin canonical ACTL6A noncanonical A/B/C polybromo ACTL6A Actin A/B/C ACTL6A PHF10 BRM/ SS18 ARID1A/B BRG1 SS18 BRG1 BRD7 BRM/ ARID2 SMARCB1 SMARC BRG1 D1 SMARCB1 SMARCD SMARCE1 SMARC SMARC S

  5. Slide 5: BRD9 Inhibition vs. Degradation

    BRD9 Inhibition vs. Degradation BRD9 associates with chromatin independent of its bromodomain, therefore traditional BRD9 inhibitors do not fully ablate oncogenic transcription Brien et al. eLife 2018 © 2021 C4 Therapeutics, Inc. 5

  6. Slide 6: Published BRD9 Degraders – Excellent In Vitro Tool Compounds

    Published BRD9 Degraders – Excellent In Vitro Tool Compounds dBRD9 VZ185 RI-1 cells (8h): BRD9 DC50 = 1.8 nM BRD7 DC50 = 4.5 nM Dmax = 95% Zoppi et al. J. Med. Chem. 2019, 62, 699 Remillard et al. Angew. Chem. Int. Ed. Engl. 2017, 56, 5738 © 2021 C4 Therapeutics, Inc.

  7. Slide 7: C4T’s Approach to BiDAC Degrader Discovery

    C4T’s Approach to BiDAC Degrader Discovery An operationally refined, information rich approach that is successful ~75% of the time Strategy: Target Lig 1 Target Lig 2 Chemistry Vector 1 Vector 1 Design 1 2 Targeting Ligands + x Target Lig 1 Target Lig 2 2 Exit Vectors Vector 2 Vector 2 Synthesis 2 F

  8. Slide 8: BRD9 BiDAC Degrader HIT

    BRD9 BiDAC Degrader HIT GOAL: Identify a drug-like compound with a mouse PK profile suitable to demonstrate proof-of-concept efficacy in a mouse xenograft model Potently degrades BRD9 Selective over BRD4 & BRD7 Drug-like properties Binds BRD9 Plasma stability Compound 1 Binds Cereblon Mouse PK BRD9-

  9. Slide 9: BRD9 BiDAC Degrader HIT: Design Objectives

    BRD9 BiDAC Degrader HIT: Design Objectives GOAL: Identify a drug-like compound with a mouse PK profile suitable to demonstrate proof-of-concept efficacy in a mouse xenograft model MW 754 Shorten linker length ClogP 4.4 (reduce MW and # rotatable bonds) Potently degrades BRD9 TPSA 194 HBD 4 Selective

  10. Slide 10: Linker Length and Composition

    Linker Length and Composition Compound Linker BRD9 DC50 Emax 2h (nM) 2h (%) 1 (HIT) 5 4 Alkyl >> PEG 2 91 3 3 3 3 4 67 4 Reduction of linker length tolerated with 5 242 23 some loss of potency 6 >9990 67 Will shorter linker lengths be tolerated with non-phthalimide CRBN binders? © 2021 C4 Therapeuti

  11. Slide 11: Shorter Linker Length Tolerated with Alternate CRBN Binder

    Shorter Linker Length Tolerated with Alternate CRBN Binder N-aryl glutarimide (Replacement for phthalimide) Compound Linker BRD9 DC50 Emax Mouse IV CL 2h, (nM) 2h (%) [mL/min/kg] 7 160 23 107 8 >9990 67 -- 9 >9990 67 -- Easy to miss degradation signal if not exploring 10 >9990 62 -- systematically 1

  12. Slide 12: How to Improve PK? Metabolite-ID for the Original HIT

    How to Improve PK? Metabolite-ID for the Original HIT Met-ID studies suggest glycyl in exit vector region is a source of metabolic instability Next SAR step Identify alternative structural feature to replace glycine © 2021 C4 Therapeutics, Inc. 12

  13. Slide 13: Glycyl Replacement Can Offer Potency & Metabolic Stability Improvement

    BRD9 DC50 Emax Mouse IV CL Glycyl Replacement Can Offer Potency Cmpd Linker 2h, (nM) 2h (%) [mL/min/kg] & Metabolic Stability Improvement 14 187 9 93 15 88 3 102 16 305 24 88 Exit Vector Linker Moiety 17 224 11 56 18 25 10 68 Goals: 19 98 18 79 Improve potency Improve metabolic stability 20 7 4 157

  14. Slide 14: Glycyl Replacement Can Offer Potency & Metabolic Stability Improvement

    BRD9 DC50 Emax Mouse IV CL Glycyl Replacement Can Offer Potency Cmpd Linker 2h, (nM) 2h (%) [mL/min/kg] & Metabolic Stability Improvement 14 187 9 93 15 88 3 102 16 305 24 88 Exit Vector Linker Moiety 17 224 11 56 2h, BRD9 HiBiT, 293T cells 18 25 10 68 19 98 18 79 20 7 4 157 Potency & PK 21 5 4 36 i

  15. Slide 15: Single Atom Change is Beneficial for Bromodomain Selectivity

    BRD9 DC50 Emax Mouse IV CL Single Atom Change is Beneficial Cmpd Linker 2h, (nM) 2h (%) [mL/min/kg] for Bromodomain Selectivity 21 5 4 36 25 15 8 154 26 158 36 10 Exit Vector Linker Moiety 27 39 5 31 Hypothesis: 28 >5000 45 42 Small modification in exit vector region 29 55 7 55 could influence exit

  16. Slide 16: Single Atom Change is Beneficial for Bromodomain Selectivity

    BRD9 DC50 Emax Mouse IV CL Single Atom Change is Beneficial Cmpd Linker 2h, (nM) 2h (%) [mL/min/kg] for Bromodomain Selectivity 21 5 4 36 25 15 8 154 26 158 36 10 Exit Vector Linker Moiety 27 39 5 31 Compound 27 Some potency 28 >5000 45 42 2h, BRD9 HiBiT, 293T cells lost….but selectivity 29 55 7 55

  17. Slide 17: Single Atom Change is Beneficial for Bromodomain Selectivity

    BRD9 DC50 Emax Mouse IV CL Single Atom Change is Beneficial Cmpd Linker 2h, (nM) 2h (%) [mL/min/kg] for Bromodomain Selectivity 21 5 4 36 25 15 8 154 26 158 36 10 27 39 5 31 28 >5000 45 42 Compound 27: Reasonable balance of potency, mouse IV PK, and selectivity 29 55 7 55 Mouse IV PK Mouse PO PK 30

  18. Slide 18: Selectivity Considerations: BRD Sequence Alignments Diverge at ZA-loop

    Selectivity Considerations: BRD Sequence Alignments Diverge at ZA-loop N-acetyl lysine ZA-loop αZ’’ binding pocket BC-loop Z” Z’ ZA-loop C Bromodomain sequences deviate within the ZA-loop near αZ’’ Modeling and HDX data suggest this region might interact with A B CRBN in the ternary complex In BRD7,

  19. Slide 19: Compound 21 Ternary Complex Model

    Compound 21 Ternary Complex Model BRD9 ZA-Loop CRBN © 2021 C4 Therapeutics, Inc. 19

  20. Slide 20: Compound 21 Ternary Complex Model

    Compound 21 Ternary Complex Model BRD7 BRD9 ZA-Loop CRBN Phe © 2021 C4 Therapeutics, Inc. 20

  21. Slide 21: Compound 21 Ternary Complex Model

    Compound 21 Ternary Complex Model BRD4 BRD7 BRD9 ZA-Loop CRBN © 2021 C4 Therapeutics, Inc. 21

  22. Slide 22: Comparing Ternary Complex Models for Compound 21 and 27

    Comparing Ternary Complex Models for Compound 21 and 27 ~1.5k TCMs generated for Compounds 21 & 27, superimposed using BRD9 (CRBN removed) Compound 21: TCMs cover broad conformational space due to flexible C-N bond in exit vector Compound 27: TCMs occupy two major clusters due to more narrowly-defin

  23. Slide 23: Comparing Ternary Complex Models for Compound 21 and 27

    Comparing Ternary Complex Models for Compound 21 and 27 ~1.5k TCMs generated for Compounds 21 & 27 superimposed using CRBN (BRD9 removed) Compound 21: Broader conformational space, larger radius sampled less selective Compound 27 : Smaller radius sampled more selective 90° © 2021 C4 Therapeutics, In

  24. Slide 24: Selectivity: Compound 27 Does Not Degrade Neomorphic Off-targets

    Selectivity: Compound 27 Does Not Degrade Neomorphic Off-targets GSPT1 SALL4 IKZF1 (G1 to S phase transition 1) (Spalt-like transcription factor 4) (Ikaros Family Zinc Finger 1) HEK 293T cells KELLY cells NCI-H929 cells Compound 1 (HIT) Compound 1 (HIT) Compound 1 (HIT) Compound 27 Compound 27 Compo

  25. Slide 25: Compound 27 Degrades Endogenous BRD9, Inhibits Synovial Sarcoma Cell Growth

    Compound 27 Degrades Endogenous BRD9, Inhibits Synovial Sarcoma Cell Growth Endogenous BRD9 Degradation Viability Effects Yamato-SS Synovial Sarcoma cells (2 hours) HSSYII Synovial Sarcoma cells (144 hours) Compound 27 % Viability Normalized to DMSO BRD9/Vinculin nM: 0 10 30 100 -BRD9 -vinculin Degr

  26. Slide 26: Compound 27 Inhibits Growth of Synovial Sarcoma Xenograft Model

    Compound 27 Inhibits Growth of Synovial Sarcoma Xenograft Model Synovial Sarcoma CDX (Yamato-SS) Activity Tolerability © 2021 C4 Therapeutics, Inc. 26

  27. Slide 27: Compound 27 is Efficacious in a PDX Model of Synovial Sarcoma

    Compound 27 is Efficacious in a PDX Model of Synovial Sarcoma Synovial Sarcoma PDX (SA13412) Activity Tolerability © 2021 C4 Therapeutics, Inc. 27

  28. Slide 28: Conclusions

    Conclusions Compound 27 is a potent and selective BiDAC degrader of BRD9 with improved drug- like properties relative to the HIT Compound 1 Compound 27 demonstrated efficacy in both cell-derived and patient-derived models of synovial sarcoma (IV or IP dosing) Compound 27 was used as a launching poin

  29. Slide 29: Thank You

    Thank You

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