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

文献类型：期刊论文

作者Li, Zhiqiang1,6; Li, Xinzhi4; Su, Ming-Bo3,6; Gao, Li-Xin6; Zhou, Yu-Bo6; Yuan, Bingchuan4; Lyu, Xilin6; Yan, Ziqin6; Hu, Chujiao5; Zhang, Hao6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-04-23
卷号63期号:8页码:4388-4407
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c00396
通讯作者Chen, Zheng(chenzheng@hit.edu.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要The overexpression of NIX 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.
WOS关键词IKK-ALPHA ; PATHWAY ; LIVER ; OVEREXPRESSION ; INFLAMMATION ; ACTIVATION ; CASCADE ; OBESITY ; DESIGN ; CANCER
资助项目National Natural Science Foundation of China[81872724] ; National Natural Science Foundation of China[81673295] ; National Natural Science Foundation of China[31671225] ; National Natural Science Foundation of China[31971083] ; National Natural Science Foundation of China[81125023] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-004-010] ; Natural Science Foundation of Heilongjiang Province[YQ2019C011] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; K. C. Wong Education Foundation ; Chinese Postoctoral Science Foundation[AUGA4130900619]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000529170200035
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/280615]  
专题新药研究国家重点实验室
通讯作者Chen, Zheng; Li, Jia; Zhao, Yujun
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, Qingdao 266237, Peoples R China
3.Nanjing Univ Chinese Med, Nanjing 210023, Jiangsu, Peoples R China
4.Harbin Inst Technol, Sch Life Sci & Technol, HIT Ctr Life Sci, Harbin 150001, Peoples R China
5.Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Guiyang 550014, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Zhiqiang,Li, Xinzhi,Su, Ming-Bo,et al. Discovery of a Potent and Selective NF-kappa B-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(8):4388-4407.
APA Li, Zhiqiang.,Li, Xinzhi.,Su, Ming-Bo.,Gao, Li-Xin.,Zhou, Yu-Bo.,...&Zhao, Yujun.(2020).Discovery of a Potent and Selective NF-kappa B-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo.JOURNAL OF MEDICINAL CHEMISTRY,63(8),4388-4407.
MLA Li, Zhiqiang,et al."Discovery of a Potent and Selective NF-kappa B-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo".JOURNAL OF MEDICINAL CHEMISTRY 63.8(2020):4388-4407.

入库方式： OAI收割

来源：上海药物研究所

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