6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site.

Massimo Ghizzoni, Jiang Wu, Tielong Gao, Hidde J Haisma, Frank J Dekker, Y George Zheng

Index: Eur. J. Med. Chem. 47 , 337-44, (2012)

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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.Copyright © 2011 Elsevier Masson SAS. All rights reserved.