新型NIK抑制剂的设计、合成及抗银屑病作用机制研究

银屑病是一种慢性自身免疫性皮肤病，影响着全世界约2-4％人口。NIK作为非经典NF-κB信号通路的核心蛋白，其过度激活在银屑病发病机制中具有直接或间接作用。以NIK为潜在银屑病治疗靶标，开发NIK抑制剂作为银屑病治疗新策略极具研究价值。前期研究我们获得了活性较好的新型NIK抑制剂I-6(IC50=9.87±0.15nM)，其在268种野生型激酶筛选实验中对NIK表现出较高选择性，一定程度上可避免脱靶带来的毒副作用。且I-6可抑制巨噬细胞NO释放(86.28±0.09%)、T细胞诱导增殖(62.29±0.04%)，能显著改善IMQ诱导的银屑病模型小鼠的疾病表型和病理特征，但化合物的代谢稳定性不佳。本项目拟在此基础上，以I-6为先导物，结合合理药物设计和类药性早期预测，对其进行结构修饰与相关生物活性评价，以期获得成药性优异、作用机制明确和对银屑病疗效突出的新型NIK抑制剂。

Psoriasis is a common chronic autoimmune dermatosis that affects approximately 2-4% of the world population. NIK, as an essential mediator in noncanonical NF-κB signaling pathway, plays a direct or indirect role in the pathogenesis of psoriasis through its dysfunction. The development of NIK inhibitors as a new strategy for psoriasis treatment, using NIK as a potential psoriasis treatment target, is of great research value. In our preliminary study, we obtained a novel NIK inhibitor I-6 (IC50=9.87±0.15nM) which showed high selectivity for NIK in 268 wild-type kinase screening assays. The result indicated that I-6 could avoid the toxic side effects of off-targeting. Moreover, I-6 inhibited macrophage NO secretion (86.28±0.09%) and T-cell proliferation (62.29±0.04%). In IMQ-induced psoriasis mice model, I-6 can significantly improve the disease phenotype and pathological characteristics. On the basis of the previous work, this project aims to optimize the lead compound I-6 and further improve the biological activity by combining rational drug design and early prediction of drug-like properties. Overall, this project will develop novel NIK inhibitors with excellent druggability, clear mechanism of action and outstanding curative effect on psoriasis.