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

doi:10.1038/s41401-022-00993-5

	Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1
	Wang, Zuo-wei 1,2; Zou, Feng-ming 1,3; Wang, Ao-li 1,3; Yang, Jing 1,3; Jin, Rui 1,3; Wang, Bei-lei 1,3; Shen, Li-juan 1,2; Qi, Shuang 1,3; Liu, Juan 1,3; Liu, Jing 1,3
刊名	ACTA PHARMACOLOGICA SINICA
	2022-10-10
关键词	AZD4547 RIPK1 inhibitors SIRS model anti-necroptosis
ISSN号	1671-4083
DOI	10.1038/s41401-022-00993-5
通讯作者	Liu, Jing(jingliu@hmfl.ac.cn) ; Wang, Wen-chao(wwcbox@hmfl.ac.cn) ; Liu, Qing-song(qsliu97@hmfl.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[32171479] ; National Natural Science Foundation of China[82104198] ; National Natural Science Foundation of China[82103976] ; Natural Science Foundation of Anhui Province[2108085QH377] ; China Postdoctoral Science Foundation[2020M671916] ; Collaborative Innovation Program of Hefei Science Center, CAS[2021HSC-CIP014] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; CASHIPS Director's Fund[YZJJZX202011] ; CASHIPS Director's Fund[YZJJ2022QN41] ; CASHIPS Director's Fund[YZJJ2021QN38] ; Youth Innovation Promotion Association of CAS[2022453] ; High Magnetic Field Laboratory of Anhui Province
WOS关键词	MIXED-LINEAGE KINASE ; DOMAIN-LIKE PROTEIN ; CELL-DEATH ; PROGRAMMED NECROSIS ; RECEPTOR ; INFLAMMATION ; MACROPHAGES ; RESPONSES
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000865683800001
资助机构	National Natural Science Foundation of China ; Natural Science Foundation of Anhui Province ; China Postdoctoral Science Foundation ; Collaborative Innovation Program of Hefei Science Center, CAS ; Frontier Science Key Research Program of CAS ; CASHIPS Director's Fund ; Youth Innovation Promotion Association of CAS ; High Magnetic Field Laboratory of Anhui Province
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/129311]
专题	中国科学院合肥物质科学研究院
通讯作者	Liu, Jing; Wang, Wen-chao; Liu, Qing-song
作者单位	1.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Peoples R China 2.Univ Sci & Technol China, Hefei 230026, Peoples R China 3.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Peoples R China 4.Precis Med Res Lab Anhui Prov, Hefei 230088, Peoples R China
推荐引用方式 GB/T 7714	Wang, Zuo-wei,Zou, Feng-ming,Wang, Ao-li,et al. Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1[J]. ACTA PHARMACOLOGICA SINICA,2022.
APA	Wang, Zuo-wei.,Zou, Feng-ming.,Wang, Ao-li.,Yang, Jing.,Jin, Rui.,...&Liu, Qing-song.(2022).Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1.ACTA PHARMACOLOGICA SINICA.
MLA	Wang, Zuo-wei,et al."Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1".ACTA PHARMACOLOGICA SINICA (2022).