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Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer

文献类型：期刊论文

作者Wang, Ao1; Luo, Xianggang2; Meng, Xin1; Lu, Zhengyu1; Chen, Kaixian1; Yang, Yushe1,2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-07-17
卷号66期号:14页码:9972-9991
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00880
通讯作者Yang, Yushe(ysyang@simm.ac.cn)
英文摘要The androgen/androgen receptor (AR) signaling pathwayplays animportant role in castration-resistant prostate cancer (CRPC). Bifunctionalagents that simultaneously degrade AR and inhibit androgen synthesisare expected to block the androgen/AR signaling pathway more thoroughly,demonstrating the promising therapeutic potential for CRPC, even enzalutamide-resistantCRPC. Herein, a series of steroid analogs were designed, synthesized,and identified as selective AR degraders, among which YXG-158 (23-h) was the most potent antitumor compound with dual functionsof AR degradation and CYP17A1 inhibition. In addition, 23-h abrogated the hERG inhibition and exhibited excellent PK profiles.In vivo, 23-h effectively inhibited the growth of hormone-sensitiveorgans in the Hershberger assay and exhibited robust antitumor efficacyboth in enzalutamide-sensitive (LNCaP/AR) and enzalutamide-resistant(C4-2b-ENZ) xenograft models. Thus, 23-h was chosen asa preclinical candidate for the treatment of enzalutamide-resistantprostate cancer.
WOS关键词GALETERONE ; PROGRESSION ; APOPTOSIS ; MOLECULE ; SURVIVAL
资助项目National Natural Science Foundation of China[82073684]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001027370600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/306701]  
专题新药研究国家重点实验室
通讯作者Yang, Yushe
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Ao,Luo, Xianggang,Meng, Xin,et al. Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(14):9972-9991.
APA Wang, Ao,Luo, Xianggang,Meng, Xin,Lu, Zhengyu,Chen, Kaixian,&Yang, Yushe.(2023).Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer.JOURNAL OF MEDICINAL CHEMISTRY,66(14),9972-9991.
MLA Wang, Ao,et al."Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer".JOURNAL OF MEDICINAL CHEMISTRY 66.14(2023):9972-9991.

入库方式： OAI收割

来源：上海药物研究所

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