Therapeutics: BET bromodomain proteins; bromodomain containing 2 (BRD2); BRD3; BRD4; von Hippel-Lindau tumor suppressor (vHL)

Cell culture and mouse studies identified a BET bromodomain protein degrader that could help treat castration-resistant prostate cancer (CRPC). Chemical synthesis and testing in three human CRPC cell lines of small molecules linking BRD4- and vHL-binding scaffolds identified a compound, ARV-771, that degraded BRD2, BRD3 and BRD4 with IC50 values less than 5 nM and decreased proliferation compared with a BET inhibitor tool compound and the BET inhibitor OTX015. In two xenograft mouse models of CRPC, ARV-771 decreased tumor growth compared with OTX015. Next steps by Arvinas LLC include testing the safety of ARV-771 in mice.

Arvinas has ARV-771 in preclinical development for CRPC...