AACR Presentation: The Discovery and Characterization of CFT8634

The Discovery and Characterization of CFT8634:

A Potent and Selective Degrader of BRD9 for the Treatment of SMARCB1-Perturbed Cancers

Katrina L. Jackson, Roman V. Agafonov, Mark W. Carlson, Prasoon Chaturvedi, David Cocozziello, Kyle Cole, Richard Deibler, Scott J. Eron, Andrew Good, Ashley A. Hart, Minsheng He, Christina S. Henderson, Hongwei Huang, Marta Isasa, R. Jason Kirby, Linda Lee, Michelle Mahler, Moses Moustakim, Christopher G. Nasveschuk, Michael Palmer, Laura L. Poling, Roy M. Pollock, Matt Schnaderbeck, Stan Spence, Gesine K. Veits, Jeremy L. Yap, Ning Yin, Rhamy Zeid, Adam S. Crystal, Andrew J. Phillips, Stewart L. Fisher

C4 Therapeutics, Inc

Watertown, MA USA

Disclosure Information

Katrina L. Jackson, PhD

• ▪ I have the following financial relationships to disclose:

  • • Stockholder in: C4 Therapeutics

  • • Employee of: C4 Therapeutics

• ▪ I will not discuss off label use and/or investigational use in my presentation.

BRD9: Drugging the Undruggable with a Heterobifunctional Degrader Approach

Strong Rationale for Degrader Approach1,2

• • Synovial sarcoma (SS) is dependent on BRD9 due to the oncogenic SS18-SSX fusion

• • Inhibition of the BRD9 bromodomain is insufficient to ablate its oncogenicity

a Patient figures represent estimated U.S. annual incidence. SS, synovial sarcoma.

1. NIH SEER Database, Primary Literature Consensus; 2. Brien GL et al. eLife. 2018;7:e41305; 3. Wang S et al. J Cancer. 2017;8(10):1759-1768.

BAF Complexes Regulate Chromatin State

Oncogenic SS18-SSX Fusion Leads to BRD9 Dependency in Synovial Sarcoma

cBAF

**Compromised**

ncBAF

** Aberrant **

Incorporation of SS18-SSX fusion results in eviction of SMARCB1

• ▪ cBAF complex compromised

• ▪ Oncogenic state

Inactivation of SMARCB1 leads to dependency on ncBAF complex

• ▪ BRD9 is uniquely present in ncBAF

• ▪ Synthetic lethal dependency on BRD9 in synovial sarcoma and other SMARCB1-deficient cancers