Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1 PMID: 36216899

ADC Targets in Oncology

2026-04-10

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. [email protected].
5. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
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. [email protected].
7. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
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. [email protected].
9. University of Science and Technology of China, Hefei, 230026, China. [email protected].
10. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
11. Precision Medicine Research Laboratory of Anhui Province, Hefei, 230088, China. [email protected].
# Contributed equally.

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.