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Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor

文献类型：期刊论文

作者Rao, Danni1,5; Li, Heng2; Ren, Xuelian3; Sun, Yaoliang1; Wen, Cuiyun1; Zheng, Mingyue4,5; Huang, He3,5; Tang, Wei2,5; Xu, Shilin1,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-07-05
卷号219页码:12
关键词Zeta-chain associated protein kinase 70 kDa (ZAP-70) Covalent inhibitor T cell Autoimmune diseases
ISSN号0223-5234
DOI10.1016/j.ejmech.2021.113393
通讯作者Tang, Wei(tangwei@simm.ac.cn) ; Xu, Shilin(slxu@simm.ac.cn)
英文摘要ZAP-70 (zeta-chain associated protein kinase 70 kDa) signaling pathway and its functions have been involved in the development and adaptive immune signaling of T cell. It thus represents a promising target for autoimmune diseases. Although reversible ZAP-70 kinase domain inhibitors have been developed, they are either weak or nonselective. We report herein the structure-guided development of the first potent and covalent inhibitor of ZAP-70 kinase domain. In particular, compound 18 (RDN009) showed good selectivity for ZAP-70 over structurally related Syk, and displayed potent inhibitory effects on T cell proliferation, activation, and inflammatory cytokine production. A mass spectrometry analysis further confirmed the covalent linkage between the inhibitor and ZAP-70 protein at C346. Overall, the covalent inhibitor RDN009 represents a potent and selective probe of ZAP-70 for further development for treatment of autoimmune diseases. (C) 2021 Elsevier Masson SAS. All rights reserved.
WOS关键词T-CELL-RECEPTOR ; TYROSINE KINASE ; PROGRESS ; BIOLOGY ; COMPLEX ; DESIGN ; DOMAIN
资助项目Natural Science Foundation of Shanghai[20ZR1468400] ; Science & Technology Commission of Shanghai Municipality, China[18431907100] ; Young Elite Scientists Sponsorship Program by CAST[2019-2021QNRC001] ; National Natural Science Foundation of China[81973164] ; Shanghai Pujiang Program[19PJ1411200] ; Shanghai Institute of Materia Medica
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000646945500002
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/297355]  
专题新药研究国家重点实验室
通讯作者Tang, Wei; Xu, Shilin
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat & Immunopharmacol, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Ctr Chem Biol, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 110039, Peoples R China
推荐引用方式
GB/T 7714		 Rao, Danni,Li, Heng,Ren, Xuelian,et al. Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,219:12.
APA Rao, Danni.,Li, Heng.,Ren, Xuelian.,Sun, Yaoliang.,Wen, Cuiyun.,...&Xu, Shilin.(2021).Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,219,12.
MLA Rao, Danni,et al."Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 219(2021):12.

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来源：上海药物研究所

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