Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors

Bioorg Med Chem. 2011 Aug 1;19(15):4626-34. doi: 10.1016/j.bmc.2011.06.030. Epub 2011 Jun 15.

Abstract

Herein we report the discovery of a family of novel yet simple, amino-acid derived class I HDAC inhibitors that demonstrate isoform selectivity via access to the internal acetate release channel. Isoform selectivity criteria is discussed on the basis of X-ray crystallography and molecular modeling of these novel inhibitors bound to HDAC8, potentially revealing insights into the mechanism of enzymatic function through novel structural features revealed at the atomic level.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetic Acid / metabolism*
  • Amino Acids / chemistry*
  • Amino Acids / pharmacology*
  • Crystallography, X-Ray
  • Drug Design
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Models, Molecular
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism

Substances

  • Amino Acids
  • Histone Deacetylase Inhibitors
  • Protein Isoforms
  • Histone Deacetylases
  • Acetic Acid