PDF(Pubmed)
Abstract：
Excessive inflammation caused by abnormal activation of the NLRP3 inflammasome contributes to the pathogenesis of multiple human diseases, but clinical drugs targeting the NLRP3 inflammasome are still not available. In this study, we identify entrectinib (ENB), a US Food and Drug Administration (FDA)-approved anti-cancer agent, as a target inhibitor of the NLRP3 inflammasome to treat related diseases. ENB specifically blocks NLRP3 without affecting activation of other inflammasomes. Furthermore, we demonstrate that ENB directly binds to arginine 121 (R121) of NEK7 and blocks the interaction between NEK7 and NLRP3, thereby inhibiting inflammasome assembly and activation. In vivo studies show that ENB has a significant ameliorative effect on mouse models of NLRP3 inflammasome-related diseases, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate (MSU)-induced peritonitis, and high-fat diet (HFD)-induced type 2 diabetes (T2D). These data show that ENB is a targeted inhibitor of NEK7 with strong anti-NLRP3 inflammasome activity, making it a potential candidate drug for the treatment of inflammasome-related diseases.
摘要：
由NLRP3炎性体异常激活引起的过度炎症有助于多种人类疾病的发病机理，但针对NLRP3炎性体的临床药物仍不可用。在这项研究中,我们确定了恩替尼（ENB），美国食品和药物管理局（FDA）批准的抗癌剂，作为NLRP3炎性体的靶向抑制剂来治疗相关疾病。ENB特异性阻断NLRP3而不影响其他炎性体的激活。此外，我们证明ENB直接与NEK7的精氨酸121（R121）结合，并阻断NEK7和NLRP3之间的相互作用，从而抑制炎症小体的组装和激活。体内研究表明，ENB对NLRP3炎症相关疾病的小鼠模型有显著的改善作用，包括脂多糖（LPS）诱导的全身性炎症，尿酸单钠（MSU）诱导的腹膜炎，高脂饮食（HFD）诱导的2型糖尿病（T2D）。这些数据表明，ENB是NEK7的靶向抑制剂，具有强抗NLRP3炎性体活性，使其成为治疗炎症相关疾病的潜在候选药物。
