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Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1)

文献类型：期刊论文

作者Zhang, Shiyan1,3; Huang, Chaoying4; Lyu, Xilin3; Wang, Peipei3; Zang, Yi3; Wang, Zengtao3; Wang, Huan3; Li, Jia1,2,3,4; Zhao, Yujun1,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-06-01
卷号195页码:13
关键词ASK1 ASK2 Selectivity Apoptosis Cell cycle arrest
ISSN号0223-5234
DOI10.1016/j.ejmech.2020.112277
通讯作者Li, Jia(jli@simm.ac.cn) ; Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要Inhibition of MAP3K kinase ASK1 has been an attractive strategy for the treatment of nonalcoholic steatohepatitis and multiple sclerosis, among others. Herein, we reported the discovery of 2-pyridinyl urea-containing compound 14l (YD57) as a potent, small-molecule inhibitor of ASK1. 14l was selective against MAP3K kinases ASK2 and TAK1 (>140-fold), while it also inhibited several cell cycle regulating kinases with IC(50 )values in a range of 90-400 nM (<20-fold selectivity). As a consequence, 14l had stronger apoptosis induction, more potent G1 cell cycle arrest activities, and lower IC50 value of cell growth inhibition than that of GS4997 in HepG2 cancer cell line. On the other hand, 14l did not inhibit ASK1 and p38 phosphorylation in intact cells. We reason that the multi-target effects of 14l likely neutralized the activities caused by inhibition of cellular ASK1. Future studies of these ASK1 inhibitors should pay close attention to their kinome selectivity profile. (C) 2020 Elsevier Masson SAS. All rights reserved.
WOS关键词FAMILY PROTEINS ; DEPENDENT ACTIVATION ; P38 ; DESIGN ; IDENTIFICATION ; STRESS ; DRUG ; THIOREDOXIN ; DERIVATIVES ; INDUCTION
资助项目National Natural Science Foundation of China[81872724] ; National Natural Science Foundation of China[81673295] ; National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81673489] ; National Natural Science Foundation of China[31871414] ; National Natural Science Foundation of China[81903429] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2019ZX09201001-003-009] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2019ZX09201001-003-010] ; Personalized medicines-molecular signature-based drug discovery and development-strategic priority research program of the Chinese Academy of Sciences[XDA12040329] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; K. C. Wong Education Foundation
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000528271200009
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/280454]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Zhao, Yujun
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Nanjing, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Shiyan,Huang, Chaoying,Lyu, Xilin,et al. Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1)[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,195:13.
APA Zhang, Shiyan.,Huang, Chaoying.,Lyu, Xilin.,Wang, Peipei.,Zang, Yi.,...&Zhao, Yujun.(2020).Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1).EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,195,13.
MLA Zhang, Shiyan,et al."Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1)".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 195(2020):13.

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来源：上海药物研究所

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