Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status

J Med Chem. 2018 Mar 22;61(6):2589-2603. doi: 10.1021/acs.jmedchem.8b00136. Epub 2018 Mar 9.


Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC50s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • CD13 Antigens / antagonists & inhibitors
  • Caspase 3 / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Genes, p53 / genetics*
  • HEK293 Cells
  • Histone Deacetylase 1 / antagonists & inhibitors*
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Leukemia / drug therapy*
  • Leukemia / genetics*
  • Male
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Molecular Docking Simulation
  • PC-3 Cells
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics*
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • CD13 Antigens
  • Caspase 3
  • HDAC1 protein, human
  • Histone Deacetylase 1