2. Academic Validation
  3. Development of dual AR/ARV7 degraders with 3,5-dimethylisoxazole to overcome antiandrogen resistance in castration-resistant prostate cancer

Development of dual AR/ARV7 degraders with 3,5-dimethylisoxazole to overcome antiandrogen resistance in castration-resistant prostate cancer

  • Eur J Med Chem. 2026 Jan 5:301:118259. doi: 10.1016/j.ejmech.2025.118259.
Rongyu Zhang 1,  Meng Wu 2,  Haojia Dong 1,  Yirong Zheng 1,  Xia Ou 1,  Xiaoxin Li 3,  Xiaoli Han 1,  Xiaodong Luan 4,  Ming Liu 5,  Jinming Zhou 6
Affiliations

Affiliations

  • 1 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China.
  • 2 Center for Drug Research and Evaluation, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, PR China.
  • 3 Stem Cell and Regenerative Medicine Lab, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, PR China.
  • 4 Center for Drug Research and Evaluation, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, PR China. Electronic address: [email protected].
  • 5 Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, PR China. Electronic address: [email protected].
  • 6 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China. Electronic address: [email protected].
PMID: 41106066 DOI: 10.1016/j.ejmech.2025.118259
Abstract

During the treatment of castration-resistant prostate Cancer (CRPC) patients, the emergence of various resistance mechanisms compromises the efficacy of second-generation antiandrogens. Recently, the targeted protein degradation (TPD) strategy has been harnessed for the development of novel AR inhibitors, aiming to overcome current resistance mechanisms. Our previous studies identified Z15 as a selective Androgen Receptor degrader (SARD). Here, we optimized the structure of Z15 and identified ZA5 as a potent dual degrader of both AR and ARV7. ZA5 directly interacts with the ligand-binding domain (LBD) and the N-terminal domain (NTD) of AR, promoting the degradation of AR/ARV7. Moreover, ZA5 effectively suppresses the transcriptional activity of wild-type AR (AR-WT), AR mutants, and ARV7, while downregulating the mRNA and protein levels of downstream AR target genes, thereby overcoming antiandrogen resistance mediated by ARV7 and AR point mutations. This study provides a potential lead compound with dual AR/ARV7 inhibitory activity, offering a novel therapeutic strategy to combat drug resistance in CRPC.

Keywords

Androgen receptor; Antiandrogen; Castration-resistant prostate cancer; Degrader; Drug resistance.

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