Cell-ELISA-Based High-Throughput Screening Leads to the Discovery of Androgen Receptor Degraders to Conquer Castration-Resistant Prostate Cancer

Androgen Receptor (AR) antagonists play a pivotal role in the treatment of castration-resistant prostate Cancer (CRPC). However, the reactivation of AR signaling during antiandrogen therapy remains a major factor contributing to resistance against currently used clinical antagonists. As a result, strategies aimed at degrading the AR protein have garnered substantial attention for CRPC therapy. In this study, we first established a high-throughput screening (HTS) model for AR degraders based on Cell-ELISA technology. Using this model to screen our in-house chemical database, we identified a novel AR degrader, ZC9. Functional evaluations demonstrated that ZC9 exhibits significant inhibitory activity against CRPC cell proliferation and effectively downregulates AR protein levels. Mechanistic studies revealed that ZC9 directly binds to AR and inhibits dihydrotestosterone (DHT)-induced nuclear translocation of AR. Furthermore, ZC9 promotes AR degradation via the ubiquitin-proteasome system (UPS) and suppresses AR transcriptional activity. Collectively, these findings highlight ZC9 as a promising lead compound for the treatment of CRPC.