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

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

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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