How BMS-986365 works in mCRPC
BMS-986365 (CC-94676) is a heterobifunctional ligand-directed degrader that targets the androgen receptor (AR) through a mechanism of degradation and antagonism.1
BMS-986365 contains an AR binding moiety to bind and antagonize the AR ligand-binding domain (LBD) connected via a short linker to a cereblon (CRBN)-binding moiety that facilitates CRL4CRBN E3 ligase-dependent ubiquitination and subsequent proteosome system-mediated irreversible AR degradation.1
BMS-986365 was intentionally designed to achieve high receptor-binding affinity while maintaining low intrinsic agonist activity and is a highly potent and selective AR degrader that induces rapid and deep degradation of both wildtype and mutant forms of the receptor.1
Pre-clinically, BMS-986365 demonstrated more potent AR inhibitory activity and anti-tumor activity than conventional AR antagonist (enzalutamide) and deep and durable tumor suppression in ARPI-resistant mCRPC models.1 This supports that BMS-986365 has the potential to overcome major resistance mechanisms such as AR gene amplification, AR LBD mutations to current androgen-targeting agents.1
BMS-986365 is a heterobifunctional molecule designed to be both a degrader and a competitive inhibitor of AR1
References
- Xu S, Nayak S, Norris JD, et al. Discovery of BMS-986365, a ligand directed androgen receptor degrader (AR LDD) with a dual mechanism-of-action and best-in-class potential, for the treatment of advanced prostate cancer. Cancer Res. 2024;84(suppl 7):ND02. In: AACR Annual Congress; San Diego, CA; 2024 Apr 5–10.
