2. Academic Validation
  3. Discovery of a Potent RXRγ Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer

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

  • J Med Chem. 2026 Apr 9;69(7):8075-8093. doi: 10.1021/acs.jmedchem.5c03442.
Chaofan Wang 1,  Jieying Lin 1,  Junping Pei 1,  Zhanfang Kang 2,  Zhuoheng Liu 1,  Junwei Li 1,  Guodi Cai 3,  Yang Zhou 1,  Junjian Wang 3 4,  Hong Wang 3,  Xiaoyun Lu 1 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
  • 2 Guangdong Engineering Technology Research Center of Urinary Continence and Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511500, China.
  • 3 National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
  • 4 State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
  • 5 Department of Hematology, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou 510632, China.
PMID: 41860027 DOI: 10.1021/acs.jmedchem.5c03442
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.

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