MAP3K7激酶共价抑制剂的研究

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.

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。

丝裂原活化蛋白激酶激酶激酶7(MAP3K7，也称TAK1)，参与了免疫和癌症细胞的关键信号通路，抑制该激酶的活性有望控制免疫细胞的功能和癌细胞的生存。本项目通过结构优化，建立新颖系列抑制剂的构效关系，发展了MAP3K7激酶的新型不可逆抑制剂；通过时间依赖性实验和稀释实验等研究了抑制剂与激酶的结合作用关系；并在多个癌症的细胞和动物模型中，实验表明所发展MAP3K7激酶抑制剂具有抑制癌细胞增殖的显著功能。MAP3K7激酶是一类免疫激酶，与其他免疫激酶在通路和功能上有着多种可能的关联。我们以激酶共价抑制剂技术发展了多个免疫系统相关激酶的抑制剂。为了化合物选择性的进一步提高，我们从新兴的蛋白降解剂和光控抑制剂的角度进行了研究，为本项目的进一步发展奠定了坚实的基础。