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

doi:10.1002/anie.202114922

	Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis
	Yang, Xiangbo 1,4; Lu, Huimin 2,4; Xie, Hang 3,6; Zhang, Binbin 4,5; Nie, Tianqing 3,6; Fan, Chen 2; Yang, Tao 2,4; Xu, Yechun 3,4,5,6; Su, Haixia 3,4; Tang, Wei 2,4
刊名	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
	2021-12-16
页码	6
关键词	Binding studies Drug discovery Necroptosis RIPK1 inhibitors Sepsis
ISSN号	1433-7851
DOI	10.1002/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.
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关键词	INTERACTING PROTEIN-1 RIP1 ; KINASE INHIBITORS ; HIGHLY POTENT ; CELL-DEATH ; NECROPTOSIS ; DISCOVERY
WOS研究方向	Chemistry
语种	英语
出版者	WILEY-V C H VERLAG GMBH
WOS记录号	WOS:000730665700001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/299187]
专题	中国科学院上海药物研究所
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.