Discovery of a Selective RXR? Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge with limited effective treatment options. We identified retinoid X receptor ? (RXR?) as a critical regulator of CRPC cell proliferation, highlighting it as a previously unrecognized and tractable target for therapeutic intervention. However, no RXR?-selective modulators have been reported. Herein, we utilized the PROTAC approach to develop WCF-598 as a selective RXR? degrader, which exhibits excellent specificity over RXRa and RXRß isoforms. WCF-598 promoted efficient RXR? degradation through the ubiquitin–proteasome system, leading to robust anti-proliferative activity in CRPC models. In vivo, WCF-598 induced significant tumor regression in 22Rv1 xenografts-bearing mice without observable toxicity. Notably, WCF-598 also exhibited a secondary activity by degrading androgen receptor splice variant 7 (AR-V7), a clinically relevant driver of therapy resistance in CRPC. These results establish WCF-598 as a selective chemical probe for investigating the function of RXR? in CRPC and potentially other RXR?-related diseases. Overall design: 22Rv1 cells treated with WCF-598 or untreated.