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Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation

文献类型：期刊论文

作者Shao, Jingwei1; Zhu, Kongkai2; Du, Daohai3; Zhang, Yuanyuan3; Tao, Hongrui2,3; Chen, Zhifeng3; Jiang, Hualiang3; Chen, Kaixian3,4; Luo, Cheng3,4; Duan, Wenhu1
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-02-15
卷号164页码:317-333
关键词PRMT5 inhibitors N-Substituted 1,2,3,4-tetrahydroisoquinoline derivatives Anti-tumor
ISSN号0223-5234
DOI10.1016/j.ejmech.2018.12.065
通讯作者Luo, Cheng(cluo@simm.ac.cn) ; Duan, Wenhu(whduan@simm.ac.cn)
英文摘要Protein arginine methyltransferases 5 (PRMT5) represents an attractive drug target in epigenetic field for the treatment of leukemia and lymphoma. Here, a series of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amide derivatives targeting PRMT5 were designed with structure-based approach and synthesized. Among them, compound 46 showed potent and selective PRMT5 inhibition activity with an IC50 of 8.5 nM, which was approximately equivalent with the phase 1 clinical trial PRMT5 inhibitor GSK-3326595 (IC50 = 5.5 nM). Compound 46 also displayed pronounced anti-proliferative activity in MV4-11 cells (GI(50) =18 nM) and antitumor activity in MV4-11 mouse xenografts model. This molecule can serve as an excellent tool compound for probing the biological function of PRMT5. (C) 2018 Published by Elsevier Masson SAS.
WOS关键词SM PROTEINS ; PRMT5 ; METHYLATION ; GROWTH ; IDENTIFICATION ; COMPLEX ; PICLN
资助项目Ministry of Science and Technology of China[2015CB910304] ; National Science and Technology Major Project[2018ZX09711002-004-013] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81803438] ; Shandong Provincial Natural Science Foundation[ZR2017BH038] ; K.C. Wong Education Foundation[XDA12020353] ; Chinese Academy of Sciences[XDA12020353] ; Science and Technology Commission of Shanghai Municipality[18431907100]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000458221400021
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/290661]  
专题新药研究国家重点实验室
通讯作者Luo, Cheng; Duan, Wenhu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
2.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res,State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Qingdao Natl Lab Marine Sci & Technol, Open Studio Drugabil Res Marine Nat Prod, Wenhai Rd, Qingdao 266237, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Shao, Jingwei,Zhu, Kongkai,Du, Daohai,et al. Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,164:317-333.
APA Shao, Jingwei.,Zhu, Kongkai.,Du, Daohai.,Zhang, Yuanyuan.,Tao, Hongrui.,...&Duan, Wenhu.(2019).Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,164,317-333.
MLA Shao, Jingwei,et al."Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 164(2019):317-333.

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来源：上海药物研究所

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