基于Menin-MLL相互作用的小分子抑制剂的研究进展

Recent progress of small-molecule inhibitors in targeting Menin-MLL interaction

多发性内分泌腺瘤1型基因编码蛋白(Menin)与混合谱系白血病(mixed lineage leukemia,MLL)融合蛋白之间的相互作用可导致急性白血病,该蛋白复合物通过调控同源异型基因(HOX)的表达,导致造血干细胞的分化能力出现障碍,继而造成MLL易位型白血病,即混合谱系白血病。有研究发现,有几类小分子化合物可以占据Menin蛋白上的MLL结合口袋,干扰Menin-MLL之间的相互作用,这一发现为此类急性白血病的治疗提供了一种新的思路。本文主要介绍Menin-MLL之间蛋白-蛋白相互作用的机制以及目前几种有前景的Menin小分子抑制剂。

The protein-protein interaction（PPI） between menin and mixed lineage leukemia （MLL） is vital to the occurence of acute leukemia. Through regulating the expression of HOX genes, Menin-MLL protein complexes affect the differentiation of hematopoietic stem cells, which lead to the MLL leukemias. Some small molecular compounds can occupy the ligand-binding pocket and then inhibit the Menin-MLL interaction, which propose a novel therapeutic strategy for MLL leukemias. This review will mainly summarize the PPI mechanism of Menin-MLL interaction and demonstrate several potential small-molecule Menin inhibitors （MI）.