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Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis

文献类型：期刊论文

作者Yang, Xiangbo1,4; Lu, Huimin2,4; Xie, Hang3,6; Zhang, Binbin4,5; Nie, Tianqing3,6; Fan, Chen2; Yang, Tao2,4; Xu, Yechun3,4,5,6; Su, Haixia3,4; Tang, Wei2,4
刊名ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
出版日期2021-12-16
页码6
关键词Binding studies Drug discovery Necroptosis RIPK1 inhibitors Sepsis
ISSN号1433-7851
DOI10.1002/anie.202114922
通讯作者Su, Haixia() ; Tang, Wei(tangwei@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要Sepsis, characterized with high risk of life-threatening organ dysfunction, represents a major cause of health loss and the World Health Organization (WHO) labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we have synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 (ZB-R-55) which is about 10-fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate.
WOS关键词INTERACTING PROTEIN-1 RIP1 ; KINASE INHIBITORS ; HIGHLY POTENT ; CELL-DEATH ; NECROPTOSIS ; DISCOVERY
资助项目National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[91753207] ; National Natural Science Foundation of China[81773568] ; Science and Technology Commission of Shanghai Municipality[20JC1418000] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[18430712500]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000730665700001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/299187]  
专题新药研究国家重点实验室
通讯作者Su, Haixia; Tang, Wei; Zhou, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 10049, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Xiangbo,Lu, Huimin,Xie, Hang,et al. Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2021:6.
APA Yang, Xiangbo.,Lu, Huimin.,Xie, Hang.,Zhang, Binbin.,Nie, Tianqing.,...&Zhou, Bing.(2021).Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,6.
MLA Yang, Xiangbo,et al."Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2021):6.

入库方式： OAI收割

来源：上海药物研究所

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