Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1  

作　　者：Zuo-wei Wang Feng-ming Zou Ao-li Wang Jing Yang Rui Jin Bei-lei Wang Li-juan Shen Shuang Qi Juan Liu Jing Liu Wen-chao Wang Qing-song Liu 

机构地区：[1]Anhui Province Key Laboratory of Medical Physics and Technology,Institute of Health and Medical Technology,Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei 230031,China [2]University of Science and Technology of China,Hefei 230026,China [3]Hefei Cancer Hospital,Chinese Academy of Sciences,Hefei 230031,China [4]Precision Medicine Research Laboratory of Anhui Province,Hefei 230088,China

出　　处：《Acta Pharmacologica Sinica》2023年第4期801-810,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant Nos,32171479,82104198,82103976);the Natural Science Foundation of Anhui Province(Grant No,2108085QH377);the China Postdoctoral Science Foundation(Grant No.2020M671916);the Collaborative Innovation Program of Hefei Science Center,CAS(Grant No.2021HSC-CIP014);the Frontier Science Key Research Program of CAS(Grant QYZDB-SSW-SLH037);the CASHIPS Director's Fund(Grant Nos.YZJZX202011,YZJJ2022QN41,YZJJ2021QN38);support of theYouth Innovation Promotion Association of CAS support(No.2022453)for JY;A portion of this work was supported by the High Magnetic Field Laboratory of Anhui Province.

摘　　要：Necroptosis is a form of regulated necrosis involved in various pathological diseases.The process of necroptosis is controlled by receptor-interacting kinase 1(RIPK1),RIPK3,and pseudokinase mixed lineage kinase domain-like protein(MLKL),and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases.In this study,using drug repurposing strategy combined with high-throughput screening(HTS),we discovered that AZD4547,a previously reported FGFR inhibitor,is able to interfere with necroptosis through direct targeting of RIPK1 kinase.In both human and mouse cell models,AZD4547 blocked RIPK1-dependent necroptosis.In addition,AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses.Together,our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.

关 键 词：AZD4547 RIPK1 INHIBITORS SIRS model anti-necroptosis 

分 类 号：R730.2[医药卫生—肿瘤]