Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy

Drug Discov Today. 2010 Mar;15(5-6):243-9. doi: 10.1016/j.drudis.2010.01.008. Epub 2010 Jan 29.


Inhibition of the proteasome (a highly abundant enzymatic complex responsible for intracellular protein turnover) is an effective anti-cancer therapeutic approach, as demonstrated by the first-in-class agent bortezomib. Various new proteasome inhibitors are now in development, including peptide boronic acid analogs MLN9708 and CEP-18770, peptide epoxyketones carfilzomib and PR-047, and NPI-0052, a beta-lactone compound. All are potent inhibitors of proteasome activity in vitro but show differences in enzyme binding kinetics, which might affect their pharmacology and result in different efficacy and safety profiles. Here, we review the second-generation proteasome inhibitors and assess the potential pharmacologic impact of their different chemical properties.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / therapeutic use
  • Boronic Acids / chemistry*
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / therapeutic use
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors*
  • Pyrazines / chemistry*
  • Pyrazines / therapeutic use


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