Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

Qin, Ying1,2; Li, Dekang1,2; Qi, Chunting1; Xiang, Huaijiang1,2; Meng, Huyan1,2; Liu, Jingli1; Zhou, Shaoqing1,2; Gong, Xinyu2,3; Li, Ying1,2,3; Xu, Guifang1; Zu, Rui1; Xie, Hang4; Xu, Yechun2,5; Xu, Gang6; Zhang, Zheng6; Chen, Shi7; Pan, Lifeng3; Li, Ying1,2,3; Tan, Li1,3

2024

10.1016/j.apsb.2023.10.021

ACTA PHARMACEUTICA SINICA B   影响因子和分区

2211-3835

2211-3843

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure -guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

RIPK1 Necroptosis Type-II kinase inhibitors Rational design Lead optimization Structure-activity relationship Anti-inflammation Preclinical drug discovery

SCI

英语

其他

National Natural Science Foundation of China["21837004","82151212","32170755"] ; Strategic Priority Research Program of the Chinese Academy of Sciences (China)[XDB39050500] ; Shanghai Municipal Science and Technology Major Project (China)[2019SHZDZX02]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:001154148000001

INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES

Web of Science

1.Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai Inst Organ Chem, Shanghai 201210, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, Shanghai 200032, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Affiliated Hosp 2, Inst Hepatol,Sch Med ,Natl Clin Res Ctr Infect Dis, Shenzhen 518112, Peoples R China
7.Shenzhen Univ, Shenzhen Peoples Hosp 2, Shenzhen Inst Translat Med, Dept Burn & Plast Surg,Affiliated Hosp 1,Med Sch, Shenzhen 518035, Peoples R China

Qin, Ying,Li, Dekang,Qi, Chunting,et al. Structure-based development of potent and selective type-II kinase inhibitors of RIPK1[J]. ACTA PHARMACEUTICA SINICA B,2024,14(1).

Qin, Ying.,Li, Dekang.,Qi, Chunting.,Xiang, Huaijiang.,Meng, Huyan.,...&Tan, Li.(2024).Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.ACTA PHARMACEUTICA SINICA B,14(1).

Qin, Ying,et al."Structure-based development of potent and selective type-II kinase inhibitors of RIPK1".ACTA PHARMACEUTICA SINICA B 14.1(2024).