Review

Deubiquitylating enzymes and drug discovery: emerging opportunities

Published online:

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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Acknowledgements

The authors thank K. Dry for extensive editing and expert advice, and other members of the S.P.J. academic laboratory for helpful discussions and advice. The authors thank L. Greger for the generation of the phylogenic tree. Research in the S.P.J. laboratory is funded by the Cancer Research UK (CRUK) Program Grant C6/A18796 and a Wellcome Trust Investigator Award (206388/Z/17/Z), and institute core infrastructure funding is provided by the CRUK (C6946/A24843) and the Wellcome Trust (WT203144).

Author information

Author notes

    • Niall M. Martin

    Present address: Artios Pharmaceuticals Ltd, Maia, Babraham Research Campus, Cambridge CB22 3AT, UK

    • Jeanine A. Harrigan
    •  & Xavier Jacq

    These authors contributed equally to this work.

Affiliations

  1. Mission Therapeutics Ltd, Moneta, Babraham Research Campus, Cambridge CB22 3AT, UK

    • Jeanine A. Harrigan
    • , Xavier Jacq
    • , Niall M. Martin
    •  & Stephen P. Jackson
  2. The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Biochemistry, Tennis Court Road, University of Cambridge, Cambridge CB2 1QN, UK.

    • Stephen P. Jackson

Authors

  1. Search for Jeanine A. Harrigan in:

  2. Search for Xavier Jacq in:

  3. Search for Niall M. Martin in:

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Competing interests

S.P.J. is part-time employed by Mission Therapeutics, Cambridge, UK, owns shares and is a director of the company. J.A.H. is a full-time employee of Mission Therapeutics. N.M.M. and X.J. own shares in Mission Therapeutics.

Corresponding author

Correspondence to Stephen P. Jackson.

Glossary

Ubiquitin

A small protein that is conjugated to other proteins (including itself) as a post-translational modification, often to control cellular signalling or degradation of the modified protein.

Ubiquitin-like proteins

(UBLs). Proteins such as small ubiquitin-like modifier (SUMO) or interferon-stimulated gene 15 (ISG15) that adopt a β-grasp fold, which is characteristic of ubiquitin and related proteins.

Proteasome

A protein complex that recognizes and degrades polyubiquitylated proteins. The 19S regulatory subunit contains ATPase- and ubiquitin-binding sites, and the 20S catalytic core contains proteases.

Deubiquitylating enzymes

(DUBs). Proteins that remove ubiquitin from substrate proteins or cleave ubiquitin precursors.

Tumour suppressor

A type of protein that normally restricts the proliferation or invasive properties of normal cells. Mutations or loss-of-expression of tumour suppressors can lead to cancer progression.

Oncogene

A type of protein that normally controls growth, differentiation or survival of cells but whose mutation or expression at abnormally high levels promotes tumorigenesis.

Isopeptidase

A type of enzyme that hydrolyses amide bonds that occur outside of the main chain in a polypeptide chain.

Regulatory T cells

(Treg cells). A subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens and prevent autoimmune disease.

Mitochondria

Cellular organelles that produce ATP through oxidative phosphorylation.

Mitophagy

The process of eliminating damaged and aged mitochondria via sequestration and hydrolytic degradation by the lysosome.

axJ

A hypomorphic allele of USP14. The ataxia mutation (axJ) is a recessive neurological mutation that results in reduced growth, ataxia and hindlimb muscle wasting in mice.

Cytokines

Members of a class of immunoregulatory proteins (interleukins or interferons) that are secreted by cells, especially cells of the immune system.

T helper cells

(TH cells). Activated T cells linked to defence against various types of pathogens, which are commonly defined by their production of particular cytokines. The best-characterized effector T cell subsets include TH1, TH2 and TH17 cells.

Allosteric

Binding to a site other than the active site of the enzyme, resulting in modulation of enzymatic activity.

Activity-based probes

(ABPs). Tools that incorporate elements for targeting, modification and/or detection of labelled proteins, enabling assessment of enzymatic activity and inhibition.