New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms

Bioorg Med Chem Lett. 2016 Sep 15;26(18):4518-4522. doi: 10.1016/j.bmcl.2016.07.041. Epub 2016 Jul 21.

Abstract

A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms.

Keywords: Bioisostere; Cyano-deaza-SAH; DOT1L inhibitors; Protein methyltransferase; Toyocamycin.

MeSH terms

  • Crystallography
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Halogens / chemistry*
  • Histone-Lysine N-Methyltransferase
  • Methyltransferases / antagonists & inhibitors*
  • Nitriles / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Halogens
  • Nitriles
  • Small Molecule Libraries
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase