Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Here we report an orally bioavailable small molecule ARV-110 that leads to ubiquitination and degradation of AR. ARV-110 completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target genes PSA and FKBP5, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting.
