Li Dong-Dong, Wang Zhi-Hui, Chen Wei-Lin, Xie Yi-Yue, You Qi-Dong, Guo Xiao-Ke
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem. 2016 Nov 15;24(22):6109-6118. doi: 10.1016/j.bmc.2016.09.073. Epub 2016 Oct 1.
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 IC value of 26.4nM in competitive binding assay and inhibiting the catalytic activity of MLL1 complex with IC value of 5.4μM. 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.
WDR5是MLL1酶活性所必需的蛋白质。靶向MLL1与WDR5之间的蛋白质-蛋白质相互作用（PPI）代表了一种针对MLL白血病的新的潜在治疗策略。基于已报道的抑制剂WDR5-0103的结构，设计并合成了一类酯化合物以干扰MLL1-WDR5 PPI。这些抑制剂在体外有效抑制组蛋白甲基转移酶活性。特别是，WL-15是最有效的抑制剂之一，在竞争性结合试验中以26.4nM的IC值阻断MLL1-WDR5的相互作用，并以5.4μM的IC值抑制MLL1复合物的催化活性。对接模型表明，酯化合物适当地占据了WDR5蛋白的中心腔，并重现了WDR5-0103的相互作用，疏水基团和关键氨基酸大大提高了阻断MLL1-WDR5 PPI的活性。
