ARV-771

ARV-771 (ARV771) is a novel and potent PROTAC-based degrader of bromodomain and extra-terminal (BET) proteins with the potential to be used in the treatment of cancers such as CRPC. It induces the degradation of BET proteins in castrate-resistent prostate cancer (CRPC) cultures (BRD2/3/4 DC50<5 nM; 22Rv1, VCaP & LnCaP95) and reduces downstream c-Myc transcription with 10-500-fold higher potency than JQ-1, OTX015, and dBET1. ARV-771 also inhibits BRD with Kd values of 4.7, 7.6, 7.6 nM against BRD2, BRD3 and BRD4, respectively. Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

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