PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Significance We describe the development of a small molecule that mediates the degradation of bromodomain and extra-terminal (BET) proteins and its application in the treatment of castration-resistant prostate cancer (CRPC). Few therapeutic options exist to treat CRPC, especially CRPC tumors expressing constitutively active androgen receptor (AR) splice variants that lack the ligand-binding domain and can effect androgen-independent transactivation of target genes. Importantly, we demonstrate that targeted degradation of BET proteins using proteolysis-targeting chimera (PROTAC) technology causes cell death in cultured prostate cancer cells and results in tumor growth inhibition or regression in mouse models of CRPC, including models that express high levels of AR splice variant 7. Our work thus contains a significant potential therapeutic advance in the treatment of this cancer.