Novel histone deacetylase 8 ligands without a zinc chelating group: exploring an 'upside-down' binding pose

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6621-7. doi: 10.1016/j.bmcl.2012.08.104. Epub 2012 Sep 7.

Abstract

A novel series of HDAC8 inhibitors without a zinc-chelating hydroxamic acid moiety is reported. Photoaffinity labeling and molecular modeling studies suggest that these ligands are likely to bind in an 'upside-down' fashion in a secondary binding site proximal to the main catalytic site. The most potent ligand in the series exhibits an IC(50) of 28 μM for HDAC8 and is found to inhibit the deacetylation of H4 but not α-tubulin in SH-SY5Y cell line.

Publication types

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

MeSH terms

  • Binding Sites
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Chelating Agents* / chemical synthesis
  • Chelating Agents* / metabolism
  • Chelating Agents* / pharmacology
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / chemistry
  • Inhibitory Concentration 50
  • Ligands
  • Molecular Structure
  • Protein Binding / drug effects
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / chemistry
  • Repressor Proteins / metabolism*
  • Zinc / chemistry

Substances

  • Chelating Agents
  • Hydroxamic Acids
  • Ligands
  • Repressor Proteins
  • HDAC8 protein, human
  • Histone Deacetylases
  • Zinc