Discovery of CFT8634, a Potent, Selective, and Orally Bioavailable Heterobifunctional Degrader of BRD9
Katrina L. Jackson, Ning Yin, Roman V. Agafonov, Prasoon Chaturvedi, Kyle S. Cole, Scott J. Eron, Andrew C. Good, June A. Hart, Minsheng He, Christina S. Henderson, Hongwei Huang, R. Jason Kirby, Linda Lee, Moses Moustakim, Christopher G. Nasveschuk, Andrew J. K. Phillips, Roy M. Pollock, Laura L. Poling, Gesine K. Veits, Jeremy Y. Yap, Rhamy Zeid, Amro Ali, Adam Crystal, Eunju Hurh, Huan Liu, Riadh Lobbardi, Leonard Reyno, Stewart L. Fisher
Abstract
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 CFT8634, an orally bioavailable heterobifunctional degrader that mediates potent and selective proteasomal degradation of BRD9. Oral dosing of CFT8634 in preclinical mouse xenograft models led to dose-dependent BRD9 degradation and tumor growth inhibition. Based on its promising preclinical profile, CFT8634 was advanced into a Phase 1 study in patients with SMARCB1-perturbed and -null tumors. CFT8634 demonstrated dose-dependent increases in human exposure with robust pharmacodynamic response but only modest efficacy outcomes in late-line patients. Further, the advancement of CFT8634 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.