Wang Leibo, Zhu Kehan, Tian Ziyang, Wang Haoyu, Jia Yulei, Feng Chunlan, Qi Luyao, Tang Wei, Hu Youhong
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
Eur J Med Chem. 2025 Feb 5;283:117125. doi: 10.1016/j.ejmech.2024.117125. Epub 2024 Dec 3.
Aberrant activation of NLRP3 inflammasome is involved in various inflammatory diseases, making it a promising target for therapeutic intervention. NEK7, a member of the NIMA-related kinase (NEK) family, functions as a key NLRP3-binding protein and plays a crucial role in the regulation of NLRP3 inflammasome assembly and activation. Thus, disrupting NLRP3-NEK7 interactions by targeting NEK7 could be a promising strategy to inhibit the activation of NLRP3 inflammasome. In this work, a series of novel urea derivatives were designed and synthesized based on the reported NEK7 inhibitors. Among these, compound 23 exhibited potent activity against IL-1β release with low cytotoxicity. Moreover, compound 23 enhanced the thermal stability of NEK7 and disrupted the NLRP3-NEK7 interaction, thereby regulating NLRP3 inflammasome assembly.
NLRP3炎性小体的异常激活与多种炎症性疾病有关，这使其成为治疗干预的一个有前景的靶点。NEK7是NIMA相关激酶（NEK）家族的成员，作为关键的NLRP3结合蛋白，在NLRP3炎性小体的组装和激活调节中起关键作用。因此，通过靶向NEK7破坏NLRP3-NEK7相互作用可能是抑制NLRP3炎性小体激活的一种有前景的策略。在这项工作中，基于已报道的NEK7抑制剂设计并合成了一系列新型尿素衍生物。其中，化合物23对IL-1β释放表现出强效活性且细胞毒性低。此外，化合物23增强了NEK7的热稳定性并破坏了NLRP3-NEK7相互作用，从而调节NLRP3炎性小体的组装。
