Discovery of a Potent and Selective NF-κB-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo

• Published in: Journal of medicinal chemistry Vol. 63; no. 8; pp. 4388 - 4407
• Main Authors: Li, Zhiqiang, Li, Xinzhi, Su, Ming-Bo, Gao, Li-Xin, Zhou, Yu-Bo, Yuan, Bingchuan, Lyu, Xilin, Yan, Ziqin, Hu, Chujiao, Zhang, Hao, Luo, Cheng, Chen, Zheng, Li, Jia, Zhao, Yujun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.04.2020; Amer Chemical Soc
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Discovery - methods; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hepatocytes - drug effects; Hepatocytes - enzymology; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; NF-kappaB-Inducing Kinase; Pharmacology & Pharmacy; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein Structure, Secondary; Science & Technology; OVEREXPRESSION; ACTIVATION; OBESITY; DESIGN; PATHWAY; INFLAMMATION; LIVER; CASCADE; IKK-ALPHA; CANCER
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00396

The overexpression of NIK plays a critical role in liver inflammatory diseases. Treatment of such diseases with small-molecule NIK inhibitors is a reasonable but underexplored approach. In this paper, we reported the discovery of a potent and selective NIK inhibitor 46 (XT2). 46 inhibited the NIK kinase with an IC50 value of 9.1 nM in vitro, and it also potently suppressed NIK activities in intact cells. In isogenic primary hepatocytes, treatment of 46 efficiently suppressed the expressions of NIK-induced genes. 46 was orally bioavailable in mice with moderate systemic exposure. In a NIK-associated mouse liver inflammation model, 46 suppressed CCl4-induced upregulation of ALT, a key biomarker of acute liver injury. 46 also decreased immune cell infiltration into the injured liver tissue. Overall, these studies provide examples that an NIK inhibitor is able to suppress toxin-induced liver inflammations, which indicates its therapeutic potentials for the treatment of liver inflammatory diseases.