Identification of benzofuran-4,5-diones as novel and selective non-hydroxamic acid, non-peptidomimetic based inhibitors of human peptide deformylase

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4528-32. doi: 10.1016/j.bmcl.2011.05.129. Epub 2011 Jun 12.

Abstract

Selective inhibitors of human peptide deformylase (HsPDF) are predicted to constitute a new class of antitumor agents. We report the identification of benzofuran-4,5-diones as the first known selective HsPDF inhibitors and we describe their selectivity profile in a panel of metalloproteases. We characterize their structure-activity relationships for antitumor activity in a panel of cancer cell lines, and we assess their in vivo efficacy in a mouse xenograft model. Our results demonstrate that selective HsPDF inhibitors based on the benzofuran-4,5-dione scaffold constitute a novel class of antitumor agents that are potent in vitro and in vivo.

Publication types

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

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity
  • Benzofurans / chemistry*
  • Benzofurans / therapeutic use
  • Benzofurans / toxicity
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / therapeutic use
  • Enzyme Inhibitors / toxicity
  • Humans
  • Hydroxamic Acids / chemistry
  • Metalloproteases / antagonists & inhibitors
  • Metalloproteases / metabolism
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Benzofurans
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Metalloproteases
  • Amidohydrolases
  • peptide deformylase
  • benzofuran