Isothiazolones; thiol-reactive inhibitors of cysteine protease cathepsin B and histone acetyltransferase PCAF

Org Biomol Chem. 2011 Mar 21;9(6):1817-22. doi: 10.1039/c0ob00464b. Epub 2011 Jan 25.

Abstract

Isothiazolones and 5-chloroisothiazolones react chemoselectively with thiols by cleavage of the weak nitrogen-sulfur bond to form disulfides. They show selectivity for inhibition of the thiol-dependent cysteine protease cathepsin B and the histone acetyltransferase p300/CBP associated factor (PCAF) based on their substitution pattern. Furthermore, enzyme kinetics and mass spectroscopy indicate covalent binding of a 5-chloroisothiazolone to cathepsin B, which demonstrates their potential utility as probes for activity-based protein profiling.

MeSH terms

  • Cathepsin B / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Sulfhydryl Compounds / chemistry*
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology
  • p300-CBP Transcription Factors / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Protease Inhibitors
  • Sulfhydryl Compounds
  • Thiazoles
  • isothiazolidinone
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Cathepsin B