Structure-based design of ester compounds to inhibit MLL complex catalytic activity by targeting mixed lineage leukemia 1 (MLL1)-WDR5 interaction

被引：21

作者：

Li, Dong-Dong ^{[1
,2
]}

Wang, Zhi-Hui ^{[1
,2
]}

Chen, Wei-Lin ^{[1
,2
]}

Xie, Yi-Yue ^{[1
,2
]}

You, Qi-Dong ^{[1
,2
,3
]}

Guo, Xiao-Ke ^{[1
,2
,3
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Jiangsu, Peoples R China

[3] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 22期

基金：

中国国家自然科学基金;

关键词：

MLL1-WDR5; interaction; Histone methyltransferase; Ester compounds; Leukemia; Docking; H3K4 METHYLTRANSFERASE ACTIVITY; COVALENT HISTONE MODIFICATIONS; WDR5-MLL INTERACTION; LYSINE METHYLATION; LEUKEMOGENESIS; OPTIMIZATION; DISRUPTION; MLL1-WDR5; PROTEIN;

D O I：

10.1016/j.bmc.2016.09.073

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

WDR5 is an essential protein for enzymatic activity of MLL1. Targeting the protein-protein interaction (PPI) between MLL1 and WDR5 represents a new potential therapeutic strategy for MLL leukemia. Based on the structure of reported inhibitor WDR5-0103, a class of ester compounds were designed and synthetized to disturb MLL1-WDR5 PPI. These inhibitors efficiently inhibited the histone methyltransferase activity in vitro. Especially, WL-15 was one of the most potent inhibitors, blocking the interaction of MLL1-WDR5 with IC50 value of 26.4 nM in competitive binding assay and inhibiting the catalytic activity of MLL1 complex with IC50 value of 5.4 mu M. Docking model indicated that ester compounds suitably occupied the central cavity of WDR5 protein and recapitulated the interactions of WDR5-0103 and the hydrophobic groups and key amino greatly increased the activity in blocking MLL1-WDR5 PPI. (C) 2016 Elsevier Ltd. All rights reserved.

引用

收藏

页码：6109 / 6118

页数：10

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