JAK3选择性抑制剂抗类风湿性关节炎的作用及其分子机制

非受体酪氨酸激酶（JAK）家族依托JAK-STAT信号通路调控机体免疫炎症反应，是近年发现治疗自免病的新靶点，目前已上市JAK抑制剂由于非选择性抑制JAK而存在明显副作用问题，所以选择性JAK抑制剂的研究尤为重要。我们前期靶向设计获得了一个结构全新的高选择性JAK3小分子抑制剂Z0583，其在激酶水平抑制JAK3活性的IC50 为0.1 nM，选择性是其它亚型的3200倍以上，同时在小鼠CIA模型显示明显的抗类风湿关节炎（RA）作用，但确切机制尚不明确。本项目拟在激酶、细胞、整体水平考察其作用于JAK3的选择性特点、探讨Z0583调控JAK3-STAT通路的作用特点，阐明Z0583靶向JAK3的作用方式、对免疫细胞的影响、及调控JAK-STAT发挥抗RA的确切机制，从而揭示JAK激酶亚型选择性与疾病的关系。本研究将为基于JAK3靶点的新一代小分子抑制剂研发奠定基础和提供科学依据。

The non-receptor tyrosine kinase (JAK) family relies on the JAK-STAT signaling pathway to regulate the immune inflammatory response. It is a new target for the treatment of autoimmune diseases in recent years. Currently, marketed JAKs inhibitors have obvious side effects due to non-selective inhibition of JAKs. So the research of selective JAK inhibitors is particularly important. In our previous work, we obtained a novel highly selective JAK3 small molecule inhibitor Z0583. Its IC50 for inhibiting JAK3 kinase activity is 0.1 nM, and the selectivity is more than 3200 times that of other JAKs. In mouse CIA model Z0583 shows a clear anti-rheumatoid arthritis effect, but the exact mechanism is still unclear. This project intends to explore the selectivity and characteristics of Z0583 in regulating JAK3-STAT pathway and the mechanism of anti-rheumatoid arthritis to clarify the mode of action and activation site and selective regulation of key molecules in the JAK3-STAT pathway. This study intends to clarify the exact mechanism by which Z0583 exerts its anti-inflammatory effects through selective regulation of the JAK3-STAT pathway, thereby revealing the relationship between the selectivity of JAK kinase subtypes and diseases. The research will lay the foundation and provide scientific basis for the development of small molecule inhibitors based on JAK3.