Abstract ND03: Discovery of ARV-766, an androgen receptor degrading PROTAC® for the treatment of men with metastatic castration resistant prostate cancer

Le résumé fourni par la source

Abstract Prostate cancer is the second leading cause of cancer death in men in the United States. The androgen receptor (AR) plays critical roles in both early disease and advanced prostate cancer. Current therapeutic approaches targeting the androgen/AR axis are initially effective, but castration resistant prostate cancer (CRPC) inevitably develops. CRPC is linked with increased AR activity via gene overexpression, amplification, and gain-of-function mutations. To address these mechanisms of AR-dependent prostate tumor growth, we have developed a novel therapeutic agent, ARV-766, a proteolysis targeting chimera (PROTAC®) that induces a protein-protein interaction between the AR and specific E3 ubiquitin ligase complexes, leading to the ubiquitination of AR and its subsequent degradation via the proteasome. In vitro, ARV-766 degrades AR in various prostate cancer cell lines, including those harboring resistance-conferring, clinically relevant point mutations, with a half-maximal degradation concentration (DC50) of <1 nM in wild type VCaP. Importantly ARV-766 also maintains potency against the AR L702H mutant, which has been associated with resistance to some AR antagonists. In vivo, ARV-766 is orally bioavailable and robustly degrades AR with a >90% observed maximum degradation (Dmax) at efficacious doses. ARV-766 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including an enzalutamide-insensitive non-castrated VCaP model. These preclinical data supported the clinical development of ARV-766 for the treatment of men with metastatic CRPC. Selected pre-clinical data along with the chemical structure of ARV-766 will be presented. Citation Format: Larry Snyder, S H. Lee, T K. Neklesa, X Chen, H Dong, C Ferraro, D A. Gordon, J Macaluso, J Pizzano, J Wang, R R. Willard, N Vitale, R Peck, M D. Moore, C M. Crews, J Houston, A P. Crew, I Taylor. Discovery of ARV-766, an androgen receptor degrading PROTAC® for the treatment of men with metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND03.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.