Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China.
Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, China.
Cell Commun Signal. 2024 Nov 25;22(1):565. doi: 10.1186/s12964-024-01919-w.
Aberrant activation of NLRP3 inflammasome is associated with a variety of inflammatory diseases. Advances in understanding the molecular mechanisms of NLRP3 inflammasome have revealed that NEK7 is an essential component for its activation, but the development of drugs specifically targeting NEK7 remains challenging. Here we identify rociletinib (ROC), an anticancer drug in phase III clinical trial with high safety profile, as a highly potent and specific small-molecule antagonists of NEK7. Mechanistically, ROC covalent binds to the cysteine 79 of NEK7 through its reactive α, β-unsaturated carbonyl group, thereby inhibiting the interaction between NLRP3 and NEK7, and the subsequent assembly and activation of NLRP3 inflammasome. Furthermore, ROC alleviates the pathological features of metainflammation on the mouse model of type 2 diabetes (T2D). In summary, our results identify ROC as a covalent inhibitor of NEK7 and demonstrates that targeting NEK7 provides a potential and promising strategy for the treatment of NLRP3 inflammasome-driven T2D.
NLRP3 炎性小体的异常激活与多种炎症性疾病有关。对 NLRP3 炎性小体分子机制的深入了解表明，NEK7 是其激活所必需的组成部分，但特异性靶向 NEK7 的药物的开发仍然具有挑战性。在这里，我们鉴定出 Rociletinib（ROC），一种处于 III 期临床试验阶段、具有高安全性的抗癌药物，是一种针对 NEK7 的高效且特异性的小分子拮抗剂。从机制上讲，ROC 通过其反应性的 α，β-不饱和羰基共价结合到 NEK7 的半胱氨酸 79 上，从而抑制 NLRP3 和 NEK7 之间的相互作用，以及 NLRP3 炎性小体的随后组装和激活。此外，ROC 减轻了 2 型糖尿病（T2D）小鼠模型中的代谢性炎症的病理特征。总之，我们的结果将 ROC 鉴定为 NEK7 的共价抑制剂，并表明靶向 NEK7 为 NLRP3 炎性小体驱动的 T2D 的治疗提供了一种有潜力和有前景的策略。
