通过构象调控方法设计MLL1-WDR5蛋白-蛋白相互作用小分子抑制剂并探索其在血液肿瘤中的应用

混合系白血病是由于组蛋白甲基转移酶MLL1的基因易位重排而引起，MLL1与WDR5结合发挥组蛋白甲基转移酶的活性对其介导的混合系白血病的发生与发展至关重要，利用小分子抑制剂干扰MLL1-WDR5的蛋白-蛋白相互作用被认为是治疗混合系白血病的有效途径。本项目针对目前MLL1-WDR5小分子抑制剂的关键问题：亟需寻找骨架结构新颖的高活性小分子抑制剂以及确证MLL1-WDR5小分子抑制剂在体内血液肿瘤中有效，针对前期研究中得到的活性较好的先导分子进行结构改造，通过构象调控的方法靶向设计、合成具有全新骨架结构的可干扰MLL1-WDR5蛋白-蛋白相互作用的小分子抑制剂，完善MLL1-WDR5蛋白-蛋白相互作用的关键作用药效特征，并由此探索该靶点在血液肿瘤中的应用，为MLL融合型白血病的研究提供参考。

Translocation of the MLL gene will lead to mixed lineage leukemia. In the process of leukemogenesis, MLL1-WDR5 protein-proteins interation plays important roles in producing methyltransferase activity. Design the small molecular inhibitor to interfere the protein-proteins interation of MLL1-WDR5 is a therapeutic strategy for acute leukemia harboring MLL fusion proteins. In this project we focus on two key problem: first is to discover the new skeleton inhibitor of MLL1-WDR5 and second is to confirm the effectivity of the inhibitor in vivo. On the basis of the lead molecular that we found in previous studies, some new skeleton inhibitors of MLL1-WDR5 will discovered by conformation regulation. This project will complete the binding mode of MLL1-WDR5, obtain Pharmacodynamic data in vivo for the first time, explore the application of MLL1-WDR5 in hemooncology and provide a reference for the next study of mixed lineage leukemia.