2. Academic Validation
  3. Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1

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

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.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13330
    99.85%, FGFR Inhibitor