Identification of histone deacetylase inhibitors with benzoylhydrazide scaffold that selectively inhibit class I histone deacetylases

Chem Biol. 2015 Feb 19;22(2):273-84. doi: 10.1016/j.chembiol.2014.12.015.

Abstract

Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Benzamides / chemistry*
  • Benzamides / metabolism
  • Benzamides / toxicity
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • HCT116 Cells
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / toxicity
  • Histone Deacetylases / chemistry*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydrazines / chemistry*
  • Hydrazines / metabolism
  • Hydrazines / toxicity
  • Kinetics
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Histone Deacetylase Inhibitors
  • Hydrazines
  • UF010 compound
  • hydrazine
  • Histone Deacetylases

Associated data

  • GEO/GSE56823