Abstract PR08: ARV-330: An androgen receptor PROTAC degrader for prostate cancer

Abstract

Abstract Patients with prostate cancer who progress on therapy often have enhanced Androgen Receptor (AR) signaling due to several mechanisms: increased androgen production, increased AR expression, and/or specific AR mutations that render current therapies ineffective. A novel approach to block AR signaling is to specifically target AR for degradation. To do this, we have created AR PROTACs (PROtein-TArgeting Chimeras), bi-functional molecules that have an AR binding moiety on one end and an E3 ligase-recruiting element on the other end, which leads to AR ubiquitination and degradation. We have applied this technology to determine whether it could address mechanisms of resistance to current therapy in prostate cancer models. Our lead AR PROTAC, ARV-330, degrades AR in LNCaP and VCaP cells with 50% degradation concentrations (DC50s) < 1nM. AR degradation had functional consequences in cells, suppressing the AR target gene PSA, inhibiting proliferation, and potently inducing apoptosis in VCaP cells, with maximal apoptosis observed around 20 nM, versus 1 uM for enzalutamide. While both ARV-330 and enzalutamide block proliferation of VCaP cells in response to 0.1 nM of the AR agonist R1881, enzalutamide lost antiproliferative potency with increasing R1881 concentrations, whereas ARV-330 maintained antiproliferative effects. In cells containing the ARF876L mutation, enzalutamide was ineffective; however, ARV-330 maintained complete effectiveness. In mice, ARV-330 exhibited good pharmacokinetic properties, with t1/2 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, resulted in reduction of AR protein levels and prostate involution in normal mice and, in mice implanted with VCaP tumors, reduction in plasma PSA and blockade of tumor growth. 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. Thus, targeted degradation of AR may provide a novel mechanism for providing efficacious therapy for patients with prostate cancer for whom current therapies have failed. Citation Format: James D. Winkler, Meizhong Jin, Andy P. Crew, AnnMarie K. Rossi, Ryan R. Willard, Hanqing Dong, Kam Siu, Jing Wang, Deborah A. Gordon, Xin Chen, Caterina Ferraro, Craig M. Crews, Kevin Coleman, Taavi K. Neklesa. ARV-330: An androgen receptor PROTAC degrader for prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR08.