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Inhibition of Zinc-Dependent Histone Deacetylases With a Chemically Triggered Electrophile

Inhibition of Zinc-Dependent Histone Deacetylases With a Chemically Triggered Electrophile

Zarko V Boskovic, Melissa M Kemp, Allyson M Freedy, Vasanthi S Viswanathan, Marius S Pop, Jason H Fuller, Nicole M Martinez, Samuel O Figueroa Lazú, Jiyoung A Hong, Timothy A Lewis, Daniel Calarese, James D Love, etc.

ACS Chem Biol. 2016 Jul 15;11(7):1844-51.

PMID: 27064299

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP315698078	BRD4354		315698-07-8	Price

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