CFT8634 is an orally bioavailable BiDAC™ degrader (or bifunctional degradation activating compound) currently in a Phase 1/2 clinical trial for the treatment of SMARCB1-perturbed cancers, including synovial sarcoma and SMARCB1-null tumors. We designed CFT8634 to be potent and selective against its intended target of BRD9, a protein that helps these certain types of cancers grow. Our preclinical research shows that CFT8634 is potent, selective and efficacious in models of synovial sarcoma and malignant rhabdoid tumors. Pharmacokinetic and pharmacodynamic data from the trial’s initial dose escalation cohorts demonstrate dose proportional exposure, strong oral bioavailability and deep BRD9 degradation.
Opportunity for Targeted Protein Degradation
Prior to the development of investigational therapies using a targeted protein degradation (TPD) approach, BRD9 was considered an “undruggable” target due to the inability of bromodomain inhibitors to effectively treat cancers dependent on BRD9. Bromodomain inhibitors only target the bromodomain; however, bromodomain occupancy is not sufficient to block BRD9-driven cancers. Unlike BRD9 inhibition, BRD9 degradation has been shown to be efficacious in preclinical models of synovial sarcoma because of its potential to remove the whole protein, including the subdomains that drive tumor formation.