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A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization

文献类型：期刊论文

作者Fu, Yuxin1,2; Jiang, Longying3; Xie, Guojian4; Peng, Yuchong5; Fu, Yongming5; Zhu, Qianling1,2; Liu, Youhong1,2; Zhao, Guilong6; Liu, Xueke3; Peng, Yongbo7
刊名COMMUNICATIONS CHEMISTRY
出版日期2025-11-18
卷号8期号:1页码:11
ISSN号2399-3669
DOI10.1038/s42004-025-01744-3
通讯作者Chen, Yongheng(yonghenc@163.com) ; Li, Xiong(lixiong@gdpu.edu.cn)
英文摘要UHRF1 is a pivotal epigenetic regulator bridging DNA methylation and histone modifications, frequently overexpressed in prostate cancer (PCa). However, no UHRF1-targeted therapeutics have advanced to clinical trials. Here, we report the development of H93, a hybrid small molecule integrating functional groups derived from NSC232003 and vorinostat, respectively. H93 exhibits potent anticancer activity in vitro, correlating with UHRF1 protein abundance, and co-crystallization studies confirm that H93 directly binding to the SRA domain of UHRF1. Intriguingly, H93 promotes UHRF1 dimerization, generating a defined binding pocket that stabilizes compound engagement and enhances druggability of UHRF1 as a non-kinase target. Dimerized UHRF1 adopts a "closed" conformation that disrupts its interaction with DNMT1, impairs DNA methylation maintenance, and reactivates epigenetically silenced tumor suppressor genes. In vivo, H93 demonstrates significant antitumor efficacy. Overall, this study elucidates the structural and mechanistic basis of H93, establishing it as a promising UHRF1-targeted therapy for PCa.
WOS关键词INCREASED SURVIVAL ; SRA DOMAIN ; DNA ; PROLIFERATION ; RECOGNITION
资助项目Research Project of Key Discipline of Guangdong Province [grant number 2019GDXK0010], National Key Specialty Construction Project of Clinical Pharmacy, High Level Clinical Key Specialty of Clinical Pharmacy in Guangdong Province [grant number 2018RS3026] a ; Hunan Provincial Science and Technology Department (Department of Science and Technology of Hunan Province)[2021RC4012] ; National Natural Science Foundation of China (National Science Foundation of China)[81572542] ; National Natural Science Foundation of China (National Science Foundation of China)[81974074] ; National Natural Science Foundation of China (National Science Foundation of China)[82172654]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001617610400005
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/322028]  
专题中国科学院上海药物研究所
通讯作者Chen, Yongheng; Li, Xiong
作者单位1.Cent South Univ, Xiangya Hosp, Xiangya Canc Ctr, Natl Clin Res Ctr Geriatr Disorders, Changsha, Peoples R China
2.Key Lab Mol Radiat Oncol Hunan Prov, Changsha 410008, Peoples R China
3.Cent South Univ, Natl Clin Res Ctr Geriatr Disorders, Dept Pathol,Xiangya Hosp, NHC Key Lab Canc Prote,State Local Joint Engn Lab, Changsha, Peoples R China
4.Changsha Hoozi Biol Sci & Technol Co Ltd, Changsha, Peoples R China
5.Guangdong Pharmaceut Univ, Affiliated Hosp 1, Key Lab Clin Precis Pharm Guangdong Higher Educ In, Guangzhou, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
7.Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China
8.Guangdong Pharmaceut Univ, Sch Basic Med Sci, Guangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Fu, Yuxin,Jiang, Longying,Xie, Guojian,et al. A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization[J]. COMMUNICATIONS CHEMISTRY,2025,8(1):11.
APA Fu, Yuxin.,Jiang, Longying.,Xie, Guojian.,Peng, Yuchong.,Fu, Yongming.,...&Li, Xiong.(2025).A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization.COMMUNICATIONS CHEMISTRY,8(1),11.
MLA Fu, Yuxin,et al."A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization".COMMUNICATIONS CHEMISTRY 8.1(2025):11.

入库方式： OAI收割

来源：上海药物研究所

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