Novel SAR for quinazoline inhibitors of EHMT1 and EHMT2

Bioorg Med Chem Lett. 2019 Sep 1;29(17):2516-2524. doi: 10.1016/j.bmcl.2019.06.012. Epub 2019 Jun 14.

Abstract

Detailed structure activity relationship of two series of quinazoline EHMT1/EHMT2 inhibitors (UNC0224 and UNC0638) have been elaborated. New and active alternatives are presented for the ubiquitous substitution patterns found in literature for the linker to the lysine mimicking region and the lysine mimic itself. These findings could allow for advancing EHMT1/EHMT2 inhibitors of that type beyond tool compounds by fine-tuning physicochemical properties making these inhibitors more drug-like. .

Keywords: EHMT1; EHMT2; Epigenetics; Histone Lysine Methyl Transferase (HMKT); Quinazoline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Histocompatibility Antigens / genetics
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Lysine / chemistry
  • Molecular Docking Simulation
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Point Mutation
  • Quinazolines / chemistry
  • Quinazolines / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Histocompatibility Antigens
  • Histones
  • Quinazolines
  • EHMT1 protein, human
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • Lysine