Identification of novel, selective, and stable inhibitors of class II histone deacetylases. Validation studies of the inhibition of the enzymatic activity of HDAC4 by small molecules as a novel approach for cancer therapy

J Med Chem. 2009 Nov 12;52(21):6782-9. doi: 10.1021/jm900555u.

Abstract

5-Aryl-2-(trifluoroacetyl)thiophenes were identified as a new series of class II HDAC inhibitors (HDACi). Further development of this new series led to compounds such as 6h, a potent inhibitor of HDAC4 and HDAC6 (HDAC4 WT IC(50) = 310 nM, HDAC6 IC(50) = 70 nM) that displays 40-fold selectivity over HDAC1 and improved stability in HCT116 cancer cells (t(1/2) = 11 h). Compounds 6h and 2 show inhibition of alpha-tubulin deacetylation in HCT116 cells at 1 microM concentration and antiproliferation effects only at concentrations where inhibition of histone H3 deacetylation is observed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Acetylation
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 2 / antagonists & inhibitors*
  • Histone Deacetylase 6
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Repressor Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology
  • Tubulin / metabolism

Substances

  • Antineoplastic Agents
  • Histones
  • Isoenzymes
  • Repressor Proteins
  • Thiophenes
  • Tubulin
  • HDAC1 protein, human
  • HDAC4 protein, human
  • HDAC6 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylase 6
  • Histone Deacetylases