Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors

J Med Chem. 2005 Aug 25;48(17):5530-5. doi: 10.1021/jm0503749.


Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn(2+)-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB), a hydroxamate-tethered phenylbutyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation. In this study, we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-11] (IC(50) in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 microM was effective in causing histone hyperacetylation and p21(WAF/CIP1) overexpression and suppressing proliferation in cancer cells.

Publication types

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

MeSH terms

  • Acetylation
  • Benzamides / chemistry
  • Cell Cycle Proteins / biosynthesis
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / chemistry
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Phenylbutyrates / chemical synthesis*
  • Phenylbutyrates / chemistry
  • Phenylbutyrates / pharmacology
  • Quantitative Structure-Activity Relationship
  • Stereoisomerism


  • Benzamides
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)benzamide
  • N-hydroxy-4-(4-phenylbutyrylamino)benzamide
  • Phenylbutyrates
  • trichostatin A
  • Histone Deacetylases