title: Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile.
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.
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
authors.forename: Zarko V
authors.initials: ZV
authors.lastname: Boskovic
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Kemp
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
authors.forename: Allyson M
authors.initials: AM
authors.lastname: Freedy
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Vasanthi S
authors.initials: VS
authors.lastname: Viswanathan
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.|Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Marius S
authors.initials: MS
authors.lastname: Pop
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Fuller
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Martinez
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Figueroa Lazú
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.|Division of Hematology/Oncology, Boston Children's Hospital , Boston, Massachusetts 02116, United States.
authors.forename: Jiyoung A
authors.initials: JA
authors.lastname: Hong
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Calarese
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: Love
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Vetere
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.|Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Koehler
mesh_terms: D000818:Animals; D002460:Cell Line; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases