Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile.
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.
|Year of Publication||
ACS Chem Biol
2016 07 15
R01 CA160860 / CA / NCI NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
U54 GM094662 / GM / NIGMS NIH HHS / United States