2. Academic Validation
  3. Discovery of novel biaryl urea derivatives against IL-1β release with low toxicity based on NEK7 inhibitor

Discovery of novel biaryl urea derivatives against IL-1β release with low toxicity based on NEK7 inhibitor

  • Eur J Med Chem. 2024 Dec 3:283:117125. doi: 10.1016/j.ejmech.2024.117125.
Leibo Wang 1,  Kehan Zhu 2,  Ziyang Tian 3,  Haoyu Wang 2,  Yulei Jia 3,  Chunlan Feng 4,  Luyao Qi 2,  Wei Tang 5,  Youhong Hu 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China.
  • 2 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.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
  • 4 Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
  • 5 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; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China. Electronic address: tangwei@simm.ac.cn.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China; State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, 198 East Binhai Road, Yantai, Shandong, 264117, China. Electronic address: yhhu@simm.ac.cn.
PMID: 39647417 DOI: 10.1016/j.ejmech.2024.117125
Abstract

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.

Keywords

Inhibitors; NEK7; NLRP3 inflammasome; NLRP3-NEK7.

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