title: HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF.
abstract: Histone acetyltransferases (HATs) play important roles in the regulation of gene expression. In this report, we describe the design, synthesis, and application of peptide CoA conjugates as selective HAT inhibitors for the transcriptional coactivators p300 and PCAF. Two inhibitors (Lys-CoA for p300 and H3-CoA-20 for PCAF) were found to be potent (IC(50) approximately = 0.5 microM) and selective (approximately 200-fold) in blocking p300 and PCAF HAT activities. These inhibitors were used to probe enzymatic and transcriptional features of HAT function in several assay systems. These compounds should be broadly useful as biological tools for evaluating the roles of HATs in transcriptional studies and may serve as lead agents for the development of novel antineoplastic therapeutics.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: O D
authors.initials: OD
authors.lastname: Lau
authors.forename: T K
authors.initials: TK
authors.lastname: Kundu
authors.forename: R E
authors.initials: RE
authors.lastname: Soccio
authors.forename: S
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.forename: E M
authors.initials: EM
authors.lastname: Khalil
authors.forename: A
authors.initials: A
authors.lastname: Vassilev
authors.forename: A P
authors.initials: AP
authors.lastname: Wolffe
authors.forename: Y
authors.initials: Y
authors.lastname: Nakatani
authors.forename: R G
authors.initials: RG
authors.lastname: Roeder
authors.forename: P A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000214:Acyl Coenzyme A / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry* / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D000214:Acyl Coenzyme A; D000970:Antineoplastic Agents; D006657:Histones; D019384:Nucleic Acid Synthesis Inhibitors; D009842:Oligopeptides; D029701:Saccharomyces cerevisiae Proteins; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D008239:Lysine