title: Structure-based design of ester compounds to inhibit MLL complex catalytic activity by targeting mixed lineage leukemia 1 (MLL1)-WDR5 interaction.
abstract: 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 IC50value of 26.4nM in competitive binding assay and inhibiting the catalytic activity of MLL1 complex with IC50value 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.
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yi-Yue
authors.initials: YY
authors.lastname: Xie
authors.affiliation: 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. Electronic address: youqidong@gmail.com.
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.affiliation: 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. Electronic address: kexin95@126.com.
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Guo
mesh_terms: D055162:Biocatalysis; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004952:Esters; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
keywords: Docking; Ester compounds; Histone methyltransferase; Leukemia; MLL1–WDR5 interaction