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Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class i histone deacetylases

Academic Article
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Overview

authors

  • Chou, C. J.
  • Herman, D.
  • Gottesfeld, Joel

publication date

  • December 2008

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clinical development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compounds have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC(50) values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compounds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with K(i) of approximately 14 nm, 15 times lower than the K(i) for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides versus hydroxamates as gene activators.

subject areas

  • Animals
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Friedreich Ataxia
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Huntington Disease
  • Isoenzymes
  • Kinetics
  • Mice
  • Neoplasm Proteins
  • Neoplasms
  • Pimelic Acids
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Identity

PubMed Central ID

  • PMC2602898

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M807045200

PubMed ID

  • 18953021
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Additional Document Info

start page

  • 35402

end page

  • 35409

volume

  • 283

issue

  • 51

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