A small molecule inhibitor of fungal histone acetyltransferase Rtt109

Bioorg Med Chem Lett. 2013 May 15;23(10):2853-9. doi: 10.1016/j.bmcl.2013.03.112. Epub 2013 Apr 4.

Abstract

The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Histone Acetyltransferases / antagonists & inhibitors*
  • Histone Acetyltransferases / metabolism
  • Molecular Structure
  • Saccharomyces / enzymology*
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Saccharomyces cerevisiae Proteins
  • Small Molecule Libraries
  • Histone Acetyltransferases
  • Rtt109 protein, S cerevisiae