靶向MLL1-WDR5蛋白-蛋白相互作用抑制剂的研究进展  

Advances of inhibitors targeting MLL1-WDR5 protein-protein interaction

作　　者：陈鑫[1,2] 杨倩 尤启冬[1,2] 郭小可[1,2] CHEN Xin;YANG Qian;YOU Qidong;GUO Xiaoke(Jiangsu Key Laboratory of Drug Design and Optimization,China Pharmaceutical University,Nanjing 211198;School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]中国药科大学江苏省药物分子设计与成药性优化重点实验室,南京211198 [2]中国药科大学药学院,南京211198

出　　处：《中国药科大学学报》2022年第2期125-136,共12页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.82173673,No.81872799);江苏省自然科学基金资助项目(No.BK20191321)。

摘　　要：Mixed lineage leukemia 1(MLL1)是组蛋白甲基转移酶SET家族的成员之一。MLL1与WDR5、RbBP5、Ash2L和DPY-30组成MLL1甲基转移酶复合物调控组蛋白H3的第4位赖氨酸的甲基化水平,对造血系统的发育和血细胞的更新至关重要。部分白血病患者体内存在因MLL1基因易位而产生的致癌蛋白——MLL1融合蛋白,MLL1融合蛋白在发挥其致癌作用时需要功能完整的MLL1酶复合物,故靶向MLL1-WDR5的蛋白-蛋白相互作用成为治疗MLL1融合型白血病的潜在策略。本文对MLL1-WDR5蛋白-蛋白相互作用的生物学机制、结构信息以及抑制剂进行了系统的总结,并结合已报道数据对该领域进行了展望,以期为后续研究提供参考。Mixed lineage leukemia 1(MLL1)is a member of the"SET"histone methyltransferases family.MLL1 methyltransferase complex,consisting of MLL1,WDR5,Rb BP5,Ash2L and DPY-30,regulates methylation level of histone H3 lysine 4 and is essential for the development of human hematopoietic system and self-renewal of blood cells.As an oncogenic protein produced by the translocation of MLL1 gene,the MLL1 fusion protein has been found in some patients with leukemia.Complete MLL1 enzyme complex is required to perform histone demethylation effect,therefore,targeting the protein-protein interaction of MLL1-WDR5 has become a potential strategy for the treatment of leukemia induced by MLL1 fusion protein.This review systematically summarizes the biological mechanism,structural information and inhibitors of MLL1-WDR5 protein-protein interaction,with a perspective based on previously reported data,aiming to provide some reference for further investigation.

关 键 词：组蛋白甲基转移酶 MLL1 蛋白-蛋白相互作用 小分子抑制剂 进展 

分 类 号：R914[医药卫生—药物化学]