Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5

Eur J Med Chem. 2016 Aug 8:118:1-8. doi: 10.1016/j.ejmech.2016.04.032. Epub 2016 Apr 13.

Abstract

MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.

Keywords: Histone methyltransfreases; Leukemia; MLL1-WDR5 interaction; Small molecular inhibitors.

MeSH terms

  • Amino Acid Sequence
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins
  • Molecular Docking Simulation
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Protein Binding / drug effects
  • Protein Conformation
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*

Substances

  • Intracellular Signaling Peptides and Proteins
  • KMT2A protein, human
  • Small Molecule Libraries
  • WDR5 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase