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
  • 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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