ARV-330: Androgen receptor PROTAC degrader for prostate cancer.

267 Background: The transition from localized prostate cancer to metastatic disease often involves modulation of the Androgen Receptor (AR). During the disease progression, patients progressing on enzalutamide or abiraterone therapy exhibit amplified AR, increased intra-tumoral androgen production or AR mutations leading to promiscuity to other ligands. Therefore, AR is still the principal driver of the disease. Methods: A novel approach to block AR signaling is to specifically target AR for degradation. To this end, we have developed the PROteolysis TArgeting Chimera (PROTAC) technology that employs hetero-bifunctional small molecules that simultaneously bind VHL E3 ubiquitin ligase and a target of interest (e.g. AR). Due to induced proximity between VHL and AR, an AR PROTAC leads to ubiquitination and subsequent degradation of AR. Results: Our lead AR PROTAC, ARV-330, degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentrations (DC 50 ) < 1nM. AR degradation suppresses the AR-target gene PSA expression, inhibits proliferation, and induces potent apoptosis in VCaP cells with maximal apoptosis observed at 20 nM. While enzalutamide loses its activity in the presence of > 0.5 nM R1881, ARV-330 maintains its activity. In cells containing the AR F876L mutation, enzalutamide is an agonist; however, ARV-330 remains effective. In fact, ARV-330 is able to degrade all clinically relevant AR mutations. ARV-330 exhibits good pharmacokinetic properties, with t 1/2 values of several hours and bioavailability of > 80% after sc injection. Treatment of mice with ARV-330, at doses ranging from 0.3 to 10 mg/kg, results in reduction of AR protein levels. The in vitro potency translates into in vivo efficacy, as ARV-330 demonstrates prostate involution in intact mice. In castrated mice implanted with VCaP tumors, ARV-330 shows robust reduction of plasma PSA and blockade of tumor growth. Conclusions: In summary, the AR PROTAC ARV-330 removes AR from prostate cancer cells in a potent manner and produces therapeutic effects as a result. This cellular efficacy has translated into biomarker activity and efficacy in animal models, and ARV-330 is now in preclinical development.