Structural biasing elements for in-cell histone deacetylase paralog selectivity

J Am Chem Soc. 2003 May 14;125(19):5586-7. doi: 10.1021/ja0341440.

Abstract

We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity.

Publication types

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

MeSH terms

  • Anilides / chemistry
  • Anilides / pharmacology
  • Dioxanes / chemical synthesis
  • Dioxanes / chemistry*
  • Dioxanes / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Structure-Activity Relationship

Substances

  • Anilides
  • Dioxanes
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • tubacin
  • Histone Deacetylases