Discovery of Novel Bifunctional Agents as Potent Androgen Receptor Antagonists and Degraders for the Treatment of Enzalutamide-Resistant Prostate Cancer
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 <b>20i</b> 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 <b>20i</b> exhibited favorable oral pharmacokinetics and a good safety profile. In the 22Rv1 xenograft models, <b>20i</b> exhibited potent antitumor activity without obvious toxicity. Taken together, these results demonstrated that <b>20i</b> might be a potential candidate for the treatment of enzalutamide-resistant PCa.
Authors
- Yunrui Feng
- Yadong Chen (ORCID: https://orcid.org/0000-0002-2189-9356)
- Zhuolin Chen
- Tao Lu (ORCID: https://orcid.org/0000-0002-4633-6058)
- Yi Luo (ORCID: https://orcid.org/0000-0002-6877-9327)
- Caiping Chen (ORCID: https://orcid.org/0000-0003-4075-5427)
- Xian Wei (ORCID: https://orcid.org/0009-0001-6185-5008)
- Yawen Fan
- Hongmei Li (ORCID: https://orcid.org/0000-0003-1981-1893)
- Yan Zhang (ORCID: https://orcid.org/0000-0002-6833-8070)
- Wenqiang Zhang (ORCID: https://orcid.org/0000-0002-0317-3914)
- Hao‐Jie Zhu (ORCID: https://orcid.org/0000-0002-2248-4419)
- Xinhao Zhang (ORCID: https://orcid.org/0000-0003-0722-7681)
- Xiaoyu Zhou (ORCID: https://orcid.org/0000-0001-9911-3088)
- Feng Tang (ORCID: https://orcid.org/0009-0001-4011-7241)
- Yu Jiao (ORCID: https://orcid.org/0000-0003-1900-8523)
- Xingru Chen
Institutions
- China Pharmaceutical University (CN)
- Simcere Pharmaceutical (China) (CN)
- Affiliated Hospital of Youjiang Medical University for Nationalities (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03043
- Citations
- 1
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 1.52
Funders
- National Natural Science Foundation of China
- China Pharmaceutical University