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ACS Chem Biol DOI:10.1021/acschembio.6b00012

Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile.

Publication TypeJournal Article
Year of Publication2016
AuthorsBošković, ŽV, Kemp, MM, Freedy, AM, Viswanathan, VS, Pop, MS, Fuller, JH, Martinez, NM, Lazú, SOFigueroa, Hong, JA, Lewis, TA, Calarese, D, Love, JD, Vetere, A, Almo, SC, Schreiber, SL, Koehler, AN
JournalACS Chem Biol
Date Published2016 07 15
KeywordsAnimals, Cell Line, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans

Unbiased binding assays involving small-molecule microarrays were used to identify compounds that display unique patterns of selectivity among members of the zinc-dependent histone deacetylase family of enzymes. A novel, hydroxyquinoline-containing compound, BRD4354, was shown to preferentially inhibit activity of HDAC5 and HDAC9 in vitro. Inhibition of deacetylase activity appears to be time-dependent and reversible. Mechanistic studies suggest that the compound undergoes zinc-catalyzed decomposition to an ortho-quinone methide, which covalently modifies nucleophilic cysteines within the proteins. The covalent nature of the compound-enzyme interaction has been demonstrated in experiments with biotinylated probe compound and with electrospray ionization-mass spectrometry.


Alternate JournalACS Chem. Biol.
PubMed ID27064299
Grant ListR01 CA160860 / CA / NCI NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
U54 GM094662 / GM / NIGMS NIH HHS / United States