Entry into a new class of potent proteasome inhibitors having high antiproliferative activity by structure-based design

J Med Chem. 2004 Sep 23;47(20):4810-3. doi: 10.1021/jm049660v.

Abstract

Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Cell Division / drug effects
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Drug Screening Assays, Antitumor / methods
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / chemistry
  • Multienzyme Complexes / metabolism
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Proteasome Endopeptidase Complex
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • 3-phenoxyphenylalanyl-3,4,5-trimethoxyphenylalanyl-valine 2-hydroxy-4-methoxybenzyl amide
  • Antineoplastic Agents
  • Cysteine Proteinase Inhibitors
  • Multienzyme Complexes
  • Oligopeptides
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex