Discovery of thiohydantoin based antagonists of androgen receptor with efficient degradation for the treatment of prostate cancer

Structure–Activity Relationship (SAR) Studies of Novel Monovalent AR/AR-V7 Dual Degraders with Potent Efficacy against Advanced Prostate Cancer

“…Given the current lack of drugs approved based on AR/AR-V7 degradation, there is a constant need to develop novel chemotypes of candidate drugs, particularly those capable of targeting non-LBD such as the N-terminus, which are expected to degrade all resistance-related AR-LBD mutations and splice variants simultaneously. − Structurally, most of the presently reported AR/AR-V7 degrader modulators are composed of a lipophilic scaffold linked to the key N -heterocycle degron indispensable for degradation activities. − Based on the above findings, we report herein the design of a new generation of nonsteroidal AR/AR-V7 degraders by replacing the steroid core of Galeterone with a privileged aryl hydantoin moiety derived from Enzalutamide (Figure ). Systematic structure–activity relationship studies with a focus on optimization of the N -heterocycle degrons resulted in a total of 55 monovalent degraders (Figure ).…”