Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer
文献类型：期刊论文
| 作者 | Wang, Ao2,3; Luo, Xianggang2,3; Wang, Yawan1; Meng, Xin3; Lu, Zhengyu2,3; Yang, Yushe2,3
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2022-09-07 |
| 页码 | 22 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c01164 |
| 通讯作者 | Yang, Yushe(ysyang@simm.ac.cn) |
| 英文摘要 | Metastatic castration-resistant prostate cancer (mCRPC) with high mortality has seriously threatened men's health. Bifunctional agents simultaneously degrade and antagonize androgen receptor (AR), display robust AR signaling pathway blockade, and show the therapeutic prospect for mCRPC. Herein, systemic structural modifications on the C-3, C-6, and C-17 positions of galeterone led to the discovery of 67-b with the dual functions of AR antagonism and degradation. In vitro, 67-b exhibited excellent antiproliferative activity and potent AR degradation activity in different PCa cells (LNCaP and 22RV1), as well as outstanding antagonistic activity against wild-type and mutant (W741L, T877A, and F876L) ARs. In vivo, 67-b effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited tumor regression in the enzalutamide-resistant (c4-2b-ENZ) xenograft model. These results confirmed 67-b to be a promising AR degrader and antagonist for the treatment of mCRPC patients. |
| WOS关键词 | GALETERONE 3-BETA-IMIDAZOLE ; SPLICE VARIANTS ; ABIRATERONE ; DEGRADATION ; DISCOVERY ; AGENTS ; ENZALUTAMIDE ; PROGRESSION ; RESISTANCE ; APOPTOSIS |
| 资助项目 | National Natural Science Foundation of China[82073684] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000860791400001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302625]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yang, Yushe |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Ao,Luo, Xianggang,Wang, Yawan,et al. Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:22. |
| APA | Wang, Ao,Luo, Xianggang,Wang, Yawan,Meng, Xin,Lu, Zhengyu,&Yang, Yushe.(2022).Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer.JOURNAL OF MEDICINAL CHEMISTRY,22. |
| MLA | Wang, Ao,et al."Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer".JOURNAL OF MEDICINAL CHEMISTRY (2022):22. |
入库方式： OAI收割
来源：上海药物研究所
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