title: 6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site.
abstract: Histone acetyltransferases are important enzymes that regulate various cellular functions, such as epigenetic control of DNA transcription. Development of HAT inhibitors with high selectivity and potency will provide powerful mechanistic tools for the elucidation of the biological functions of HATs and may also have pharmacological value for potential new therapies. In this work, analogs of the known HAT inhibitor anacardic acid were synthesized and evaluated for inhibition of HAT activity. Biochemical assays revealed novel anacardic acid analogs that inhibited the human recombinant enzyme Tip60 selectively compared to PCAF and p300. Enzyme kinetics studies demonstrated that inhibition of Tip60 by one such novel anacardic acid derive, 20, was essentially competitive with Ac-CoA and non-competitive with the histone substrate. In addition, these HAT inhibitors effectively inhibited acetyltransferase activity of nuclear extracts on the histone H3 and H4 at micromolar concentrations.
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ghizzoni
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.forename: Tielong
authors.initials: T
authors.lastname: Gao
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
authors.forename: Y
authors.initials: Y
authors.lastname: George Zheng
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D000074443:Lysine Acetyltransferase 5; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D012459:Salicylates / Q000737:chemistry* / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors; D000099224:p300-CBP-Associated Factor
chemical_list: D000105:Acetyl Coenzyme A; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D000074443:Lysine Acetyltransferase 5; D012459:Salicylates; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C098489:KAT5 protein, human
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