Drugging the undruggables: exploring the ubiquitin system for drug development

Cell Res. 2016 Apr;26(4):484-98. doi: 10.1038/cr.2016.31. Epub 2016 Mar 22.


Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system (UPS). Similar to kinases, components of the ubiquitin system are often dysregulated, leading to a variety of diseases, including cancer and neurodegeneration, making them attractive drug targets. However, so far there are only a handful of drugs targeting the ubiquitin system that have been approved by the FDA. Here, we review possible therapeutic intervention nodes in the ubiquitin system, analyze the challenges, and highlight the most promising strategies to target the UPS.

Publication types

  • Review

MeSH terms

  • Drug Discovery*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • Ubiquitin / metabolism*
  • Ubiquitination / drug effects


  • Proteasome Inhibitors
  • Ubiquitin
  • Proteasome Endopeptidase Complex