Deubiquitylating enzymes and drug discovery: emerging opportunities

Nat Rev Drug Discov. 2018 Jan;17(1):57-78. doi: 10.1038/nrd.2017.152. Epub 2017 Sep 29.


More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials. However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging. In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration.

Publication types

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

MeSH terms

  • Deubiquitinating Enzymes / antagonists & inhibitors*
  • Drug Discovery / methods*
  • Drug Discovery / trends
  • Drug Industry
  • Drugs, Investigational / therapeutic use
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / enzymology
  • Proteasome Endopeptidase Complex / metabolism
  • Ubiquitin / metabolism*


  • Drugs, Investigational
  • Ubiquitin
  • Deubiquitinating Enzymes
  • Proteasome Endopeptidase Complex