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.

NIK是非经典NF-kB通路的关键调节蛋白，其激活失调已被证明是多种自身免疫性疾病和炎症性疾病的致病因素之一。然而，其相应的抑制剂开发面临诸多障碍，包括已知抑制剂结构类型的缺乏、化合物体外活性评价方法不成熟等。本研究通过合理设计和化学合成得到了一系列喹啉衍生物。其中，代表性化合物17c和24c对LPS诱导的巨噬细胞（J774）一氧化氮释放和抗Con A刺激的原代T细胞增殖具有优异的抑制活性。该评价方法具有良好的普适性，在一定程度上克服了当前抑制剂研究面临的上述障碍。此外，首次评估了该化合物在非应激条件下对T细胞生长的毒性，作为研究的指标，以避免潜在的安全风险。对毒性较小的化合物24c的药代动力学性质评价证实了其良好的代谢行为（尤其是口服性质，F% = 21.7%）以及后续的开发价值。