Discovery of a Potent RXRγ 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 γ (RXRγ) as a critical
regulator of CRPC cell proliferation, highlighting it as a previously
unrecognized and tractable target for therapeutic intervention. However,
no RXRγ-selective modulators have been reported. Herein, we
utilized the PROTAC approach to develop WCF-598 as a potent RXRγ
degrader, which exhibits preferential degradation of RXRγ over
RXRα and RXRβ isoforms. WCF-598 promoted efficient RXRγ
degradation through the ubiquitin-proteasome system, leading to robust
antiproliferative activity in CRPC models. In vivo, WCF-598 induced
significant tumor regression in 22Rv1 xenograft-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 specific chemical probe for investigating the function
of RXRγ in CRPC and potentially other RXRγ-related diseases.