Discovery of a Potent RXRγ Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer

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Abstract
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.
Funding Information
  • Sun Yat-sen University (2020B1212060034)
  • Sun Yat-sen University (24xkjc016)
  • Guangzhou Medical University (202301-212)
  • National Key Research and Development Program of China (2024YFA1307504)
  • Changjiang Scholar Program, Ministry of Education
  • Basic and Applied Basic Research Foundation of Guangdong Province (2024B1515040007)
  • Basic and Applied Basic Research Foundation of Guangdong Province (2025A1515011034)
  • Jinan University
  • National Natural Science Foundation of China (82273956)
  • National Natural Science Foundation of China (82304520)

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