ARV-378

ARV-378 is an early-stage, orally bioavailable proteolysis-targeting chimera (PROTAC) designed to induce the selective degradation of the androgen receptor (AR). Developed by Arvinas, the compound was primarily investigated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). ARV-378 functions by recruiting an E3 ubiquitin ligase (typically Cereblon in Arvinas' AR platform) to the androgen receptor, leading to the protein's polyubiquitination and subsequent degradation by the 26S proteasome. This targeted protein degradation (TPD) approach is intended to overcome resistance mechanisms associated with traditional AR antagonists, such as AR mutations or overexpression. Preclinical data demonstrated that ARV-378 could achieve potent AR degradation and inhibit tumor growth in various prostate cancer models. However, Arvinas ultimately prioritized other AR degraders, such as ARV-110 (bavdegalutamide) and the second-generation candidate ARV-766, for clinical advancement, leading to the discontinuation of ARV-378's development.