Abstract
MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50 = 0.19 μM) in HMT assay.
Keywords:
Biphenyl inhibitors; Gene expression; Histone methyltransferase; Leukemia; MLL1-WDR5 interaction.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
MeSH terms
-
Apoptosis / drug effects
-
Biphenyl Compounds / chemical synthesis
-
Biphenyl Compounds / chemistry
-
Biphenyl Compounds / metabolism
-
Biphenyl Compounds / pharmacology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Dihydropyridines / chemical synthesis
-
Dihydropyridines / chemistry
-
Dihydropyridines / metabolism
-
Dihydropyridines / pharmacology*
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacology*
-
Gene Expression Regulation / drug effects
-
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
-
Histone-Lysine N-Methyltransferase / chemistry
-
Histone-Lysine N-Methyltransferase / metabolism*
-
Histones / chemistry
-
Histones / metabolism*
-
Homeodomain Proteins / genetics
-
Humans
-
Intracellular Signaling Peptides and Proteins
-
Molecular Docking Simulation
-
Myeloid Ecotropic Viral Integration Site 1 Protein
-
Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
-
Myeloid-Lymphoid Leukemia Protein / metabolism*
-
Neoplasm Proteins / genetics
-
Protein Binding / drug effects
-
Protein Conformation
Substances
-
Biphenyl Compounds
-
Dihydropyridines
-
Enzyme Inhibitors
-
Histones
-
Homeodomain Proteins
-
Intracellular Signaling Peptides and Proteins
-
KMT2A protein, human
-
MEIS1 protein, human
-
Myeloid Ecotropic Viral Integration Site 1 Protein
-
Neoplasm Proteins
-
OICR-9429
-
WDR5 protein, human
-
homeobox protein HOXA9
-
Myeloid-Lymphoid Leukemia Protein
-
Histone-Lysine N-Methyltransferase