A novel class of small molecule inhibitors of HDAC6

ACS Chem Biol. 2012 Feb 17;7(2):331-9. doi: 10.1021/cb200134p. Epub 2011 Nov 11.


Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified in vitro. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor's selective toxicity against leukemia.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / enzymology
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*


  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Small Molecule Libraries
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases