Discovery of Novel Bifunctional Agents as Potent Androgen Receptor Antagonists and Degraders for the Treatment of Enzalutamide-Resistant Prostate Cancer

  • J Med Chem. 2025 Apr 24;68(8):8330-8345. doi: 10.1021/acs.jmedchem.4c03043.
Wenqiang Zhang  1 ,  Hao Zhu  2 ,  Zhuolin Chen  1 ,  Hongmei Li  1 ,  Xingru Chen  1 ,  Yawen Fan  1 ,  Xiaoyu Zhou  1 ,  Yi Luo  1 ,  Yan Zhang  1  3  4 ,  Feng Tang  3  4 ,  Xinhao Zhang  1 ,  Yunrui Feng  1 ,  Tao Lu  1  2 ,  Xian Wei  5 ,  Yadong Chen  1 ,  Caiping Chen  2 ,  Yu Jiao  1
Affiliations
  • 1. School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
  • 2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 3. State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd, 699-18 Xuan Wu Avenue, Nanjing 210042, China.
  • 4. Jiangsu Simcere Pharmaceutical Co., Ltd, 699-18 Xuan Wu Avenue, Nanjing 210042, China.
  • 5. Department of pharmacy, Youjiang Medical University for Nationalities, No. 98 ChengXiang Road, Youjiang, Baise 533000, Guangxi Zhuang Autonomous Region, China.
PMID: 40231807 DOI: 10.1021/acs.jmedchem.4c03043
Abstract

Bifunctional agents that simultaneously antagonize and degrade various AR proteins more effectively block the AR signaling pathway, offering a promising strategy for the treatment of mCRPC patients. Herein, we report the discovery and development of a series of small-molecule AR degraders with 3,8-diazabicyclo[3.2.1]octan scaffold. The optimal compound 20i exhibited potent AR antagonistic and degrading activities, effectively overcoming multiple resistance mechanisms and showing significant antiproliferative effects against enzalutamide-resistant PCa cell lines. Moreover, compound 20i exhibited favorable oral pharmacokinetics and a good safety profile. In the 22Rv1 xenograft models, 20i exhibited potent antitumor activity without obvious toxicity. Taken together, these results demonstrated that 20i might be a potential candidate for the treatment of enzalutamide-resistant PCa.

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