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

Zuo-wei Wang1,2, Feng-ming Zou1,3, Ao-li Wang1,3, Jing Yang1,3, Rui Jin1,3, Bei-lei Wang1,3, Li-juan Shen1,2, Shuang Qi1,3, Juan Liu1,3, Jing Liu1,3, Wen-chao Wang1,3, Qing-song Liu1,2,3,4
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
Correspondence to: Jing Liu:, Wen-chao Wang:, Qing-song Liu:,
DOI: 10.1038/s41401-022-00993-5
Received: 16 May 2022
Accepted: 30 August 2022
Advance online: 10 October 2022


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.
Keywords: AZD4547; RIPK1; inhibitors; SIRS model; anti-necroptosis

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