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

Leibo Wang; Kehan Zhu; Ziyang Tian; Haoyu Wang; Yulei Jia; Chunlan Feng; Luyao Qi; Wei Tang; Youhong Hu

doi:10.1016/j.ejmech.2024.117125

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. Online ahead of print.

Authors

Leibo Wang¹, Kehan Zhu², Ziyang Tian³, Haoyu Wang², Yulei Jia³, Chunlan Feng⁴, Luyao Qi², Wei Tang⁵, Youhong Hu⁶

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.