Synthesis and biological testing of novel pyridoisothiazolones as histone acetyltransferase inhibitors

Bioorg Med Chem. 2011 Jun 15;19(12):3678-89. doi: 10.1016/j.bmc.2011.01.063. Epub 2011 Feb 2.

Abstract

We present a combination of database screening, synthesis and in vitro testing to identify novel histone acetyltransferase (HAT) inhibitors. The National Cancer Institute compound collection (NCI) and several commercial databases were filtered by similarity-based virtual screening to find new HAT inhibitors. Employing the recombinant HAT p300/CBP-associated factor (PCAF) and two different histone substrates for screening, pyridoisothiazolones were identified as inhibitors of human PCAF. Due to the limited solubility of the initial hits, we synthesized and tested them on PCAF. The compounds inhibit the proliferation of cancer cells. In summary, valuable chemical tools and potential lead candidates for new anticancer agents directed against HATs as new targets have been identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Histone Acetyltransferases / antagonists & inhibitors*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemistry*
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Pyridines
  • Thiazoles
  • 3-isothiazolone
  • Histone Acetyltransferases