1. Academic Validation
  2. The discovery of quinoline derivatives, as NF-κB inducing kinase (NIK) inhibitors with anti-inflammatory effects in vitro, low toxicities against T cell growth

The discovery of quinoline derivatives, as NF-κB inducing kinase (NIK) inhibitors with anti-inflammatory effects in vitro, low toxicities against T cell growth

  • Bioorg Med Chem. 2021 Jan 1;29:115856. doi: 10.1016/j.bmc.2020.115856.
Jianing Song 1 Yuqin Zhu 2 Weidong Zu 2 Chunqi Duan 2 Junyu Xu 2 Fei Jiang 2 Xinren Wang 2 Shuwen Li 2 Chenhe Liu 2 Qianqian Gao 2 Hongmei Li 2 Yanmin Zhang 2 Weifang Tang 2 Tao Lu 3 Yadong Chen 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 3 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: lutao@cpu.edu.cn.
  • 4 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: ydchen@cpu.edu.cn.
Abstract

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.

Figures
Products