|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Bošković, 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|
|Journal||ACS Chem Biol|
|Date Published||2016 Jul 15|
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 Journal||ACS Chem. Biol.|