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

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

  • J Med Chem. 2020 Apr 23;63(8):4388-4407. doi: 10.1021/acs.jmedchem.0c00396.
Zhiqiang Li 1 2,  Xinzhi Li 3,  Ming-Bo Su 1 4,  Li-Xin Gao 1,  Yu-Bo Zhou 1,  Bingchuan Yuan 3,  Xilin Lyu 1,  Ziqin Yan 1,  Chujiao Hu 5,  Hao Zhang 1,  Cheng Luo 1,  Zheng Chen 3,  Jia Li 1 2 4 6,  Yujun Zhao 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
  • 4 Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
  • 6 Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China.
PMID: 32216342 DOI: 10.1021/acs.jmedchem.0c00396
Abstract

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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