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

doi:10.1021/acs.jmedchem.0c00396

	Discovery of a Potent and Selective NF-kappa B-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo
	Li, Zhiqiang 1,4; Li, Xinzhi 6; Su, Ming-Bo 4,5; Gao, Li-Xin 4; Zhou, Yu-Bo 4; Yuan, Bingchuan 6; Lyu, Xilin 4; Yan, Ziqin 4; Hu, Chujiao 3; Zhang, Hao 4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-04-23
卷号	63 期号:8 页码:4388-4407
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	IKK-ALPHA ; PATHWAY ; LIVER ; OVEREXPRESSION ; INFLAMMATION ; ACTIVATION ; CASCADE ; OBESITY ; DESIGN ; CANCER
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000529170200035
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280615]
专题	中国科学院上海药物研究所
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.Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Guiyang 550014, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Nanjing Univ Chinese Med, Nanjing 210023, Jiangsu, Peoples R China 6.Harbin Inst Technol, Sch Life Sci & Technol, HIT Ctr Life Sci, Harbin 150001, 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.