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.

坏死性凋亡是一种参与多种病理疾病的调节性坏死。坏死性凋亡过程由受体相互作用激酶 1 (RIPK1)、RIPK3 和假激酶混合谱系激酶结构域样蛋白 (MLK​​L) 控制，这些激酶的药理抑制已被证明在多种疾病中具有治疗潜力。在这项研究中，我们利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 激酶来干扰坏死性凋亡。在人和小鼠细胞模型中，AZD4547 阻断 RIPK1 依赖性坏死性凋亡。此外，AZD4547 使动物免于 TNF 诱导的致命性休克和炎症反应。总之，我们的研究表明 AZD4547 是一种有效的选择性 RIPK1 抑制剂，具有治疗坏死性凋亡相关炎症性疾病的潜力。