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.
University of Science and Technology of China, Hefei, 230026, China.
Acta Pharmacol Sin. 2023 Apr;44(4):801-810. doi: 10.1038/s41401-022-00993-5. Epub 2022 Oct 10.
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.
细胞程序性坏死是一种参与多种病理疾病的调控性细胞坏死形式。细胞程序性坏死的过程受到受体相互作用激酶 1（RIPK1）、RIPK3 和假激酶混合谱系激酶结构域样蛋白（MLKL）的控制，药理学抑制这些激酶已被证明在多种疾病中具有治疗潜力。在这项研究中，我们使用药物再利用策略结合高通量筛选（HTS），发现先前报道的 FGFR 抑制剂 AZD4547 能够通过直接靶向 RIPK1 激酶来干扰细胞程序性坏死。在人和小鼠细胞模型中，AZD4547 阻断了 RIPK1 依赖性细胞程序性坏死。此外，AZD4547 可挽救 TNF 诱导的致命性休克和炎症反应中的动物。总之，我们的研究表明，AZD4547 是一种有效的 RIPK1 选择性抑制剂，具有治疗涉及细胞程序性坏死的炎症性疾病的潜力。
