Isothiazolones; thiol-reactive inhibitors of cysteine protease cathepsin B and histone acetyltransferase PCAF.
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.
Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Rosalina
R
Wisastra
Massimo
M
Ghizzoni
Harm
H
Maarsingh
Adriaan J
AJ
Minnaard
Hidde J
HJ
Haisma
Frank J
FJ
Dekker
D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
D002401:Cathepsin B; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C512915:isothiazolidinone