The persisting challenge of selective and specific proteasome inhibition

J Pept Sci. 2009 Feb;15(2):58-66. doi: 10.1002/psc.1107.


Since the discovery of the proteasome and its structure elucidation intensive research programs in academic institutions and pharmaceutical industries led to identification of a wide spectrum of synthetic and natural small proteasomal inhibitors. Activity studies with these small molecules helped to deeply understand the complex biochemical organization and functioning of the proteasome. The new structural and biochemical insights placed the proteasome as an important anti-cancer drug target, as revealed by the dipeptide boronate proteasome inhibitor, bortezomib, which is currently used for treatment of multiple myeloma. Serious side effects and partial cell resistance against bortezomib demand creation and discovery of new improved generations of more specific and potent proteasomal inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Boronic Acids / adverse effects
  • Boronic Acids / chemistry
  • Boronic Acids / metabolism
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Catalytic Domain
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Multiple Myeloma / drug therapy*
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / metabolism
  • Protease Inhibitors* / therapeutic use
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors*
  • Protein Conformation
  • Pyrazines / adverse effects
  • Pyrazines / chemistry
  • Pyrazines / metabolism
  • Pyrazines / therapeutic use*


  • Boronic Acids
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib
  • Proteasome Endopeptidase Complex