Recent Results Cancer Res. 2014:201:325-45. doi: 10.1007/978-3-642-54490-3_20.


The ubiquitin-mediated degradation of proteins in numerous cellular processes, such as turnover and quality control of proteins, cell cycle and apoptosis, transcription and cell signaling, immune response and antigen presentation, and inflammation and development makes the ubiquitin-proteosome systems a very interesting target for various therapeutic interventions. Proteosome inhibitors were first synthesized as tools to probe the function and specificity of this particle's proteolytic activities. Most synthetic inhibitors rely on a peptide base, which mimics a protein substrate, attached at a COOH terminal "warhead." Notable warheads include boronic acids, such as bortezomib and epoxy ketones, such as carfilzomib. A variety of natural products also inhibit the proteosome that are not peptide-based, most notably lactacystin, that is related to NPI-0052, or salinosporamide A, another inhibitor in clinical trials. The possibility that proteosome inhibitors could be drug candidates was considered after studies showed that they induced apoptosis in leukemic cell lines. The first proteasome inhibitor in clinical application, bortezomib showed activity in non-small-cell lung and androgen-independent prostate carcinoma, as well as MM and mantle cell and follicular non-Hodgkin's lymphoma. It is now licensed for the treatment of newly diagnosed as well as relapsed/progressive MM and has had a major impact on the improvement in the treatment of MM in the last few years.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Humans
  • Multiple Myeloma / drug therapy*
  • Neoplasms / drug therapy
  • Proteasome Inhibitors / therapeutic use*
  • Pyrazines / therapeutic use*


  • Antineoplastic Agents
  • Boronic Acids
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib