2. Academic Validation
  3. Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile

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

  • ACS Chem Biol. 2016 Jul 15;11(7):1844-51. doi: 10.1021/acschembio.6b00012.
Zarko V Boskovic 1 2,  Melissa M Kemp 1,  Allyson M Freedy 1 2,  Vasanthi S Viswanathan 1,  Marius S Pop 3 4,  Jason H Fuller 1,  Nicole M Martinez 1,  Samuel O Figueroa Lazú 1,  Jiyoung A Hong 1 3 5,  Timothy A Lewis 1,  Daniel Calarese 6,  James D Love 6,  Amedeo Vetere 1,  Steven C Almo 6,  Stuart L Schreiber 1 2,  Angela N Koehler 1 3 4
Affiliations

Affiliations

  • 1 Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
  • 2 Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
  • 3 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
  • 4 Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
  • 5 Division of Hematology/Oncology, Boston Children's Hospital , Boston, Massachusetts 02116, United States.
  • 6 Department of Biochemistry, Albert Einstein College of Medicine , Bronx, New York 10461, United States.
PMID: 27064299 DOI: 10.1021/acschembio.6b00012
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.

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