丝裂原活化蛋白激酶激酶激酶7(MAP3K7)参与免疫和癌症细胞的关键信号通路，抑制该激酶的活性可以有效控制免疫细胞的功能和癌细胞的生存；但是MAP3K7的抑制剂研究尚在起步阶段，已报道的化合物在细胞活性和选择性方面有着明显欠缺。本申请建立在前期工作已经发现的新颖共价抑制剂基础上，集中进行三方面研究：一、进一步结构优化，确立构效关系，发展MAP3K7激酶的新型共价抑制剂；二、构建MAP3K7激酶的共价探针，发展与抑制剂的联用方法，研究抑制剂在细胞中的靶标占有率，以及该激酶的更新速度；三、在多个癌症的细胞和动物模型中，研究新发展的MAP3K7激酶共价抑制剂的抑癌功能与机制。

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7) is involved in critical signal transduction pathways in immune and cancer cells. Inhibition of this kinase activity can effectively modulate immune cells' functions and survival of cancer cells. However, the development of MAP3K7 inhibitors is still in the early stage, reported inhibitors have noticable defects in cellular activity and/or selectivity. This application is a continuation of our early exploration work, and will focus on three areas: 1. to further optimize inhibitors' structure, establish structure-activity relationship, and develop novel covalent inhibitors of MAP3K7; 2. to evelop covalent probes for MAP3K7, study inhibitors' target occupancy rate, and MAP3K7's turnover rate; 3. to examine newly-developed inhibitors in multiple cellular and animal disease models, validate MAP3K7's role as an anti-cancer target.