C4 Therapeutics, Inc. · NASDAQ:CCCC
C4 Therapeutics — Technical Presentation (2023)
16 slides from C4 Therapeutics's technical presentation, 2023
Slide 1: The Discovery and Characterization of CFT1946: Degrader of Mutant BRAF
The Discovery and Characterization of CFT1946: A Potent, Selective, and Orally Bioavailable Degrader of Mutant BRAF for the Treatment of BRAF-driven Cancers Yanke Liang on behalf of the C4T BRAF Project Team C4 Therapeutics, Inc. Watertown, MA
Slide 2: Disclosure Information
Disclosure Information Yanke Liang, Ph.D. ▪ I have the following financial relationships to disclose: • Stockholder in: C4 Therapeutics, Inc. • Employee of: C4 Therapeutics, Inc.
Slide 3: Mechanism of Action for BRAF-V600X Driven Human Cancers
Mechanism of Action for BRAF-V600X Driven Human Cancers NORMAL CONDITION BRAF-V600X CONDITION Mechanism of BRAF-V600X Driven Cancer • BRAF is a serine/threonine protein kinase in the MAPK pathway that promotes cell proliferation and survival when activated through extracellular signals • Constitutiv
Slide 4: Utilizing a Degrader Approach to Overcome Limitations of BRAF Inhibition
Utilizing a Degrader Approach to Overcome Limitations of BRAF Inhibition Advantages of BRAF Degrader Rationale V600X Degradation • Specifically target mutant BRAF- V600X over wildtype BRAF Inhibitor causes paradoxical • Prevent mutant BRAF-V600X activation of incorporation into RAF dimers wildtype R
Slide 5: Scaffold Hopping to Address Pharmacokinetics (PK) and Solubility Challenge
Scaffold Hopping to Address Pharmacokinetics (PK) and Solubility Challenge Binds BRAF Binds CRBN Binds BRAF Binds CRBN Scaffold hopping Compound 1 Azaindole core Compound 2 (medchem previously described) Quinazolinone core Mouse IV Cl = 10.8 mL/min/kg Mouse IV Cl = 1.8 mL/min/kg PO DN_AUC = 152 (ng*
Slide 6: Rigidifying Spacer Region Improved Degradation Efficiency and PK
Rigidifying Spacer Region Improved Degradation Efficiency and PK Compound 3 Compound 4 Rotatable Bonds 15 ▼ 12 BRAF-V600E DC50 / Emax [6 h] 71 nM / 28% 53 nM / 19% Mouse IV Cl [mL/min/kg] 12.8 3.5 Mouse F [%] 14 40 Ternary Complex Modeling BRAF BiDAC degrader with spirocyclic spacer: Poses for Compo
Slide 7: Binary Binding Potency on Both Ends of a BiDAC Degrader Impacted Degradation Efficiency
Binary Binding Potency on Both Ends of a BiDAC Degrader Impacted Degradation Efficiency BRAF binder BRAF binder Compound 5 Compound 2 Scaffold Azaindole Quinazolinone BRAF-V600E Ki [nM] 17 ▼ 0.1 CRBN FP Kd [nM] 92 96 BRAF-V600E 8 nM / 18% 92 nM / 41% DC50 / Emax [6 h] Ki, inhibitory constant; FP, fl
Slide 8: Binary Binding Potency on Both Ends of a BiDAC Degrader Impacted Degradation Efficiency
Binary Binding Potency on Both Ends of a BiDAC Degrader Impacted Degradation Efficiency CRBN binder CRBN binder BRAF binder BRAF binder Compound 5 Compound 2 Compound 6 Compound 7 Scaffold Azaindole Quinazolinone Quinazolinone Quinazolinone BRAF-V600E Ki [nM] 17 ▼ 0.1 0.2 0.6 CRBN FP Kd [nM] 92 96 4
Slide 9: Hydrophobic Collapse Improved Oral Bioavailability
Hydrophobic Collapse Improved Oral Bioavailability Applied to quinazolinone series X = N, Compound 8, tPSA 226, F 65% CFT1946, F 89% Azaindole core X = CH, Compound 9, tPSA 203, F 5% Quinazolinone core Solvent Accessible Surface Area (SASA) analysis Compound 8 Compound 9 Hypothesis: ▪ In the context
Slide 10: CFT1946 Displays A Balanced Preclinical Profile
CFT1946 Displays A Balanced Preclinical Profile Proteome Profiling Demonstrates Selectivity of CFT1946 for BRAF-V600E CFT1946 (300 nM, 24 h) in A375 Cells CFT1946 15 8,760 proteins BRAF-V600E DC50 / Emax [24 h] 14 nM / 26% - Log10 p-value vs. dabrafenib A375 NRASQ61K * pERK 1 h [nM] 42 10 A375 NRASQ
Slide 11: CFT1946 is an On-Mechanism, CRBN-Based, BRAF-V600X BiDAC Degrader
CFT1946 is an On-Mechanism, CRBN-Based, BRAF- V600X BiDACTM Degrader CFT1946 Degrades BRAF-V600E CFT1946 is an On-Mechanism BiDACTM in a Dose Dependent Manner Degrader CFT1946 (100 nM) in A375 cells @ 24 h 100 Targeting CRBN % Remaining 75 BRAF-V600E (24 h) Ligand Ligand MLN4924 Bortezomib DMSO 10 m
Slide 12: CFT1946 Causes BRAF-V600E Degradation, Potent Inhibition of MAPK Signaling, & Loss of Viability
CFT1946 Causes BRAF-V600E Degradation, Potent Inhibition of MAPK Signaling, & Loss of Viability in BRAF-V600E Cells but Not in WT-BRAF Cells BRAF-V600E Degradation by CFT1946 Causes CFT1946 Treatment of WT-BRAF Cells Has Loss of MAPK Signaling Superior to Inhibition Alone No Effect on MAPK Pathway a
Slide 13: CFT1946 Induces Tumor Regression in the BRAF-V600E A375 Xenograft Mouse Model
CFT1946 Induces Tumor Regression in the BRAF-V600E A375 Xenograft Mouse Model in Accordance with PK/PD Results CFT1946 Treatment of A375 Cell Line in vivo Shows Dose-Dependent Tumor Dose Proportional PK and PD for CFT1946 Regression Superior to Inhibitor Observed After Single Dose PO Treatment B-RAF
Slide 14: CFT1946 is Active in BRAF-V600E/NRAS-Q61K, a Model of Clinical Resistance
CFT1946 is Active in BRAF-V600E/NRAS-Q61K, a Model of Clinical Resistance to BRAF Inhibitors Combination Treatment of BRAFi Resistant Xenograft CFT1946 as a Single Agent and in Combination with MEKi is Model with CFT1946 and MEKi Shows Tumor Growth Effective in MAPK Pathway Inhibition, Superior to B
Slide 15: Summary
Summary CFT1946 is a potent and mutant-selective BiDACTM degrader of BRAF-V600E and superior to inhibitors in in vitro and in vivo models with BRAF-V600E–driven disease and in the escape mutant BRAF-V600E/NRAS-Q61K–driven model. The medicinal chemistry path leading to CFT1946 demonstrates that it is
Slide 16: Acknowledgments
Acknowledgments Thank you to the C4T scientists & our CRO partners across the globe who made this work possible