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Cited by 940Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsProtease and Inhibitor Mechanisms

Deubiquitylating enzymes and drug discovery: emerging opportunities

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Harrigan, Jeanine A., Jacq, Xavier, Martin, Niall M., Jackson, Stephen P.·2018·Nature Reviews Drug Discovery
DOI 10.1038/nrd.2017.152PMC PMC7097658
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Abstract

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.

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  • The ubiquitin-proteasome system controls core signaling factor abundance by selective degradation, mediates many processes in embryonic development, and aberrant UPS-dependent degradation is involved in carcinogenesis.

    “The ubiquitin-proteasome system (UPS) provides an essential way to control core signaling factor abundance by selective degradation, such that it mediates many processes in embryonic development, also aberrant regulations of UPS-dependent degradation are involved in different pathological processes especially carcinogenesis22,23.”

    From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [23]

    The Main section describes selective degradation through the UPS, and “DUBs in oncology” links dysregulated ubiquitin regulation to tumorigenesis. The paper does not establish the claimed role of UPS-dependent degradation in many embryonic-development processes; its developmental examples concern specific DUBs. Page numbers are unavailable in our copy. (LLM, conf=0.85)

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Authors
Harrigan, J. A., Jacq, X., Martin, N. M., & Jackson, S. P.
Affiliations
  • Mission Therapeutics (United Kingdom) (GB)
  • University of Cambridge (GB)
Corresponding author
Jackson, Stephen P.
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2017-09-29
Volume
17
Issue
1
Pages
57-78
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/nrd.2017.152
PMC
PMC7097658
OpenAlex
W2757682641
Cited by
940
References
15
Citations by year
2026: 95 · 2025: 172 · 2024: 132 · 2023: 115 · 2022: 122 · 2021: 101 · 2020: 97 · 2019: 62 · 2018: 39 · 2017: 3
FWCI
5.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (WT203144, Z/17/Z, C6946/A24843, 203144/A/16/Z, 206388/Z/17/Z, 203144/Z/16/Z)
  • Cancer Research UK (C6946/A24843, 18796, C6/A18796, C6946, A24843)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
deubiquitinase, DUB inhibitors, selective enzyme inhibitors, ubiquitin-proteasome system, proteasome inhibitors, E3 ubiquitin ligase, drug development, cancer, neurodegenerative diseases, infectious diseases, therapeutic target
MeSH terms
Deubiquitinating Enzymes, Drug Industry, Humans, Neoplasms, Drugs, Investigational, Neurodegenerative Diseases, Ubiquitin, Proteasome Endopeptidase Complex, Drug Discovery, Molecular Targeted Therapy

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