High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity

Eur J Med Chem. 2016 Nov 29:124:480-489. doi: 10.1016/j.ejmech.2016.08.036. Epub 2016 Aug 20.

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.

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