类风湿关节炎(rheumatoid arthritis,RA)是一种以关节炎为特征的慢性自身免疫性疾病。它是当前国内主要的公共健康问题之一。布鲁顿酪氨酸蛋白激酶(BTK)和两面神受体激酶(JAK3)是治疗RA的新型靶点。BTK抑制剂和JAK3抑制剂联用在临床上表现出一定的协同疗效，同时，同属非受体酪氨酸家族的BTK和JAK3，氨基酸序列在ATP结合域附近存在一个半胱氨酸残基。因此，针对BTK激酶和JAK3激酶开发高选择性的双靶点不可逆抑制剂将是针对RA的一种有效的治疗手段。本项目拟结合前期研究基础，采用计算机辅助药物设计的方法，设计并合成一系列BTK和JAK3双靶点抑制剂，并结合生物活性测试实验进行构效关系探讨，同时通过结构生物学实验，确认先导化合物与BTK和JAK3蛋白的共价结合方式。以期获得至少1个高选择性、低毒、双靶点BTK和JAK3不可逆抑制剂。

Rheumatoid arthritis (RA) is a kind of chronic autoimmune disease characterized by arthritis. It is one of the most significant public health focus in China. Bruton tyrosine kinase (BTK) and Janus kinase receptor(JAK3) are two novel targets for the treatments of RA. The combined treatment of BTK inhibitors and JAK3 inhibitors on RA shows a synergistic effect clinically, moreover, a cysteine residue is found in the two targets’ amino acid sequences near the ATP-binding domain while they are both belonging to non-receptor tyrosine family. Accordingly, developing a high selective and irreversible inhibitor for the BTK and JAK3 kinases would be a promising treatment strategy of RA. With the help of computer-aided drug design technologies and using the preliminary studies for reference, we intend to design and synthesize a series of BTK and JAK3 daul inhibitors, and then explore their structure-activity relationships by bioassay experiments, meanwhile confirming the covalent-binding pattern between leading compounds with BTK/ JAK3 protein by structural biology experiments. The project aims at gaining at least one highly efficient and low toxic molecule, thus providing new ideas and important basis for further researches and applications of BTK and JAK3 inhibitors.