American Chemical Society
jm0c00396_si_001.pdf (7.84 MB)

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

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journal contribution
posted on 2020-04-07, 19:35 authored by Zhiqiang Li, Xinzhi Li, Ming-Bo Su, Li-Xin Gao, Yu-Bo Zhou, Bingchuan Yuan, Xilin Lyu, Ziqin Yan, Chujiao Hu, Hao Zhang, Cheng Luo, Zheng Chen, Jia Li, Yujun Zhao
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.