Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

J Med Chem. 2018 Nov 21;61(22):10000-10016. doi: 10.1021/acs.jmedchem.8b01087. Epub 2018 Nov 8.


Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Catalytic Domain*
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / chemistry*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / metabolism
  • Hydroxamic Acids / pharmacology
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology
  • Molecular Dynamics Simulation
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / chemistry*
  • Repressor Proteins / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Triazoles / chemistry
  • Triazoles / metabolism
  • Triazoles / pharmacology


  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • N-hydroxy-3-(1-(phenylthio)methyl-1H-1,2,3-triazol-4-yl)benzamide
  • PCI 34051
  • Repressor Proteins
  • Triazoles
  • HDAC8 protein, human
  • Histone Deacetylases