Highly potent and selective histone deacetylase 6 inhibitors designed based on a small-molecular substrate

J Med Chem. 2006 Aug 10;49(16):4809-12. doi: 10.1021/jm060554y.

Abstract

To find novel histone deacetylase 6 (HDAC6)-selective inhibitors and clarify the structural requirements for HDAC6-selective inhibition, we prepared thiolate analogues designed based on the structure of an HDAC6-selective substrate and evaluated the histone/alpha-tubulin acetylation selectivity by Western blot analysis. Aliphatic compounds 17b-20b selectively caused alpha-tubulin acetylation over histone H4 acetylation. In enzyme assays using HDAC1, HDAC4, and HDAC6, compounds 17a-19a exhibited HDAC6-selective inhibition over HDAC1 and HDAC4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • HCT116 Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology
  • Tubulin / metabolism

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Sulfhydryl Compounds
  • Tubulin