Discovery of a Potent and Selective NF-kappa B-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo
Discovery of a Potent and Selective NF-kappa B-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo
复制标题
发现一种有效且选择性的 NF-κ B 诱导激酶 (NIK) 抑制剂，该抑制剂在体外和体内均具有抗炎作用
DOI：
10.1021/acs.jmedchem.0c00396
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发表时间：
2020
影响因子：
7.3
通讯作者：
Zhao Yujun
中科院分区：
文献类型：
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作者：
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
Nik的过度表达在肝脏炎症性疾病中起重要作用。使用小分子Nik抑制剂治疗此类疾病是一种合理但未被探索的方法。在本文中，我们发现了一种有效和选择性的Nik抑制剂46(XT2)。46在体外抑制Nik激酶，其IC50值为9.1 nM，并能有效地抑制完整细胞中的Nik活性。在同基因的原代肝细胞中，46的治疗有效地抑制了Nik诱导的基因的表达。46在中度全身暴露的小鼠中是口服生物利用的。在Nik相关的小鼠肝脏炎症模型中，46抑制了CCl4诱导的ALT上调，ALT是急性肝损伤的关键生物标志物。46还减少了免疫细胞对受损肝组织的渗透。总体而言，这些研究提供了NIK抑制剂能够抑制毒素诱导的肝脏炎症的例子，这表明其在治疗肝脏炎症性疾病方面具有治疗潜力。
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 inhibitor46(XT2).46inhibited the NIK kinase with an IC50value of 9.1 nM in vitro, and it also potently suppressed NIK activities in intact cells. In isogenic primary hepatocytes, treatment of46efficiently suppressed the expressions of NIK-induced genes.46was orally bioavailable in mice with moderate systemic exposure. In a NIK-associated mouse liver inflammation model,46suppressed CCl4-induced upregulation of ALT, a key biomarker of acute liver injury.46also 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.