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Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors

文献类型：期刊论文

作者Chen, Yuting1,3; Shi, Qiongyu4; Yang, Hong2; Li, Jiayi3,5; Zhou, Kaixin2,3,6; Zhang, Junjie1,3; Wang, Zekun2,3; Shi, Huanyu1,3; Xiong, Bing1,3; Liu, Jia1,5
刊名BIOORGANIC CHEMISTRY
出版日期2023
卷号130页码:20
关键词Epigenetic PRMT5 inhibitor Nucleoside derivatives Structure-activity Relationship Prodrug
ISSN号0045-2068
DOI10.1016/j.bioorg.2022.106228
通讯作者Xiong, Bing(bxiong@simm.ac.cn) ; Liu, Jia(jia.liu@simm.ac.cn) ; Huang, Xun(xhuang@simm.ac.cn) ; Liu, Tongchao(tongchao_liu@simm.ac.cn)
英文摘要Protein arginine methyltransferase 5 (PRMT5) is a promising target for the treatment of malignant tumors. The discovery of nucleoside-derived inhibitors against PRMT5 with novel scaffold has been challenging. Herein, we report our effort on the design and synthesis of nucleoside derivatives bearing sulfonamide scaffold as potent PRMT5 inhibitors. The representative compound 23n was identified as a potent and selective PRMT5 inhibitor with an IC50 value of 8 nM. Molecular docking study demonstrated the binding mode of compound 23n and illustrated its inhibitory activity to PRMT5. The Trimethyl Lock prodrug strategy was used to afford prodrug 36 with lower polarity which could rapidly release the active compound 23n after entering the tumor cells. Cell -based assays revealed that the prodrug 36 restrained the proliferation of Z-138 and MOLM-13 cells and sup-pressed methylation of PRMT5 substrate more potently than 23n. Additionally, both compound 23n and 36 exerted antiproliferative effects against Z-138 cells mainly by inducing apoptosis effectively rather than arresting cell cycle. Thus, compounds 23n and 36 represent a series of potent PRMT5 inhibitor with novel scaffold.
WOS关键词ARGININE METHYLTRANSFERASE 5 ; IN-VIVO ; METHYLATION ; GROWTH ; TARGET
资助项目Shanghai Municipal Science and Technology Major Project[TM202101H010] ; National Natural ScienceFoundation of China[21922707] ; General Program of National Natural Science Foundation of China[82173835] ; National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Open Program of State Key Laboratory of new Drug development[SIMM2105KF-04] ; SA-SIBS Scholarship Program ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000890739100005
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/304300]  
专题新药研究国家重点实验室
通讯作者Xiong, Bing; Liu, Jia; Huang, Xun; Liu, Tongchao
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Lingang Lab, Shanghai 200031, Peoples R China
5.UCAS, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Yuting,Shi, Qiongyu,Yang, Hong,et al. Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors[J]. BIOORGANIC CHEMISTRY,2023,130:20.
APA Chen, Yuting.,Shi, Qiongyu.,Yang, Hong.,Li, Jiayi.,Zhou, Kaixin.,...&Liu, Tongchao.(2023).Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors.BIOORGANIC CHEMISTRY,130,20.
MLA Chen, Yuting,et al."Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors".BIOORGANIC CHEMISTRY 130(2023):20.

入库方式： OAI收割

来源：上海药物研究所

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