Discovery of CFT8634, a Potent, Selective, and Orally Bioavailable Heterobifunctional Degrader of BRD9
The chromatin factor bromodomain-containing protein 9 (BRD9) is a genetic dependency in SMARCB1-perturbed or SMARCB1-null cancers including synovial sarcoma. In such cancers, the degradation of BRD9 is hypothesized to result in an anticancer effect. Here, we report the discovery and characterization of <b>CFT8634</b>, an orally bioavailable heterobifunctional degrader that mediates potent and selective proteasomal degradation of BRD9. Oral dosing of <b>CFT8634</b> in preclinical mouse xenograft models led to dose-dependent BRD9 degradation and tumor growth inhibition. Based on its promising preclinical profile, <b>CFT8634</b> was advanced into a Phase 1 study in patients with SMARCB1-perturbed and -null tumors. <b>CFT8634</b> demonstrated dose-dependent increases in human exposure with robust pharmacodynamic response but only modest efficacy outcomes in late-line patients. Further, the advancement of <b>CFT8634</b> as a monotherapy was inhibited by the emergence of cardiac toxicities. Nevertheless, this first study of an orally bioavailable BRD9 degrader recapitulates preclinical pharmacokinetic and pharmacodynamic observations in a clinical trial setting.
Authors
- Eunju Hurh (ORCID: https://orcid.org/0000-0001-8189-5093)
- Roy M. Pollock (ORCID: https://orcid.org/0000-0002-6182-6725)
- Riadh Lobbardi (ORCID: https://orcid.org/0000-0002-8310-7991)
- Minsheng He
- Christopher G. Nasveschuk (ORCID: https://orcid.org/0000-0003-4671-6939)
- Prasoon Chaturvedi (ORCID: https://orcid.org/0009-0002-4322-2933)
- Katrina L. Jackson (ORCID: https://orcid.org/0000-0003-3884-9723)
- Leonard Reyno
- Jeremy Y. Yap
- Adam Crystal (ORCID: https://orcid.org/0000-0002-2302-2654)
- Gesine K. Veits
- Moses Moustakim (ORCID: https://orcid.org/0000-0002-5006-5684)
- Scott J. Eron (ORCID: https://orcid.org/0000-0002-3981-9588)
- Stewart L. Fisher (ORCID: https://orcid.org/0009-0005-5167-5213)
- June A. Hart (ORCID: https://orcid.org/0009-0006-1786-259X)
- Kyle S. Cole
- Andrew J. K. Phillips (ORCID: https://orcid.org/0000-0003-1156-7056)
- Linda Lee (ORCID: https://orcid.org/0000-0003-4471-7284)
- Christina S. Henderson
- Roman V. Agafonov (ORCID: https://orcid.org/0000-0002-7765-899X)
- Laura L. Poling (ORCID: https://orcid.org/0009-0009-0918-8736)
- Rhamy Zeid
- Huan Liu (ORCID: https://orcid.org/0000-0002-9947-6687)
- Ning Yin (ORCID: https://orcid.org/0000-0001-7139-3399)
- Amro Ali (ORCID: https://orcid.org/0000-0002-1249-2175)
- Hongwei Huang (ORCID: https://orcid.org/0000-0001-8269-4461)
- Andrew C. Good (ORCID: https://orcid.org/0009-0001-9910-6475)
- R. Jason Kirby
Institutions
- C4 Therapeutics (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01317
- Citations
- 3
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.42