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

Acta Pharmacol Sin. 2022 Oct 10. doi: 10.1038/s41401-022-00993-5.

Zuo-Wei Wang ^# ¹ ², Feng-Ming Zou ^# ¹ ³, Ao-Li Wang ^# ¹ ³, Jing Yang ¹ ³, Rui Jin ¹ ³, Bei-Lei Wang ¹ ³, Li-Juan Shen ¹ ², Shuang Qi ¹ ³, Juan Liu ¹ ³, Jing Liu ⁴ ⁵, Wen-Chao Wang ⁶ ⁷, Qing-Song Liu ⁸ ⁹ ¹⁰ ¹¹

Affiliations

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 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. jingliu@hmfl.ac.cn.
5 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. jingliu@hmfl.ac.cn.
6 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. wwcbox@hmfl.ac.cn.
7 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. wwcbox@hmfl.ac.cn.
8 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. qsliu97@hmfl.ac.cn.
9 University of Science and Technology of China, Hefei, 230026, China. qsliu97@hmfl.ac.cn.
10 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. qsliu97@hmfl.ac.cn.
11 Precision Medicine Research Laboratory of Anhui Province, Hefei, 230088, China. qsliu97@hmfl.ac.cn.
# Contributed equally.

PMID: 36216899 DOI: 10.1038/s41401-022-00993-5

Abstract

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; SIRS model; anti-necroptosis; inhibitors.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-13330

Fexagratinib

99.85%, FGFR Inhibitor

FGFR

Cancer

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