体内
药理学
体外
炎症
下调和上调
化学
激酶
免疫系统
肝损伤
促炎细胞因子
IC50型
免疫学
生物化学
医学
生物
基因
生物技术
作者
Zhiqiang Li,Xinzhi Li,Mingbo Su,Lixin Gao,Yubo Zhou,Bingchuan Yuan,Xilin Lyu,Ziqin Yan,Chujiao Hu,Hao Zhang,Cheng Luo,Zheng Chen,Jia Li,Yujun Zhao
标识
DOI:10.1021/acs.jmedchem.0c00396
摘要
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.
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