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Drug discovery in the ubiquitin–proteasome system

Key Points

  • The ubiquitin–proteasome pathway promotes the degradation of proteins by first catalysing the formation of a polyubiquitin chain on the target protein. This chain is then recognized by the proteasome, allowing the target protein to be degraded. Cancer cells seem to be much more sensitive to inhibition of the proteasome than normal cells. Recent studies have revealed that peptide inhibitors of the proteasome have efficacy as antitumour agents in humans for particular types of cancer (for example, multiple myeloma). This brings the ubiquitin–proteasome system to the forefront as a target for drug discovery.

  • The ubiquitin–proteasome pathway contains a large number of components which function in specific biochemical pathways. Some of these components, such as E1-activating enzymes, are conventional enzymes and are therefore potentially amenable to drug development, whereas other components of the system are non-conventional targets for which extensive work will be required to assess their suitability as drug targets.

  • Much of our understanding of how the ubiquitin–proteasome pathway is deregulated in human disease comes from the cancer field, where it is found that certain ubiquitin ligases are overexpressed in tumours and promote the degradation of negative regulators of cell proliferation. In principle, inhibition of some of these central regulators (SKP2 and MDM2) could serve to reduce cell proliferation, and these types of molecules represent important clinical targets.

  • The other class of alteration represents mutations in ubiquitin ligases which negatively affect their activities. In the cancer setting, mutations have been found in ubiquitin ligases in cancer, including the BRCA1 and FBW7 proteins. These types of defects will be much harder to develop drugs for because it would require reactivation of a non-functional allele. Such mutations have also been seen in other classes of diseases, including Parkinson's disease in which the parkin ubiquitin ligase has been found to be mutated in its E2-binding domain.

  • Recent work using chemical library approaches to identify compounds that inhibit protein degradation have led to the realization that the polyubiquitin chain itself can be a drug target. Ubistatin is a small molecule that interacts specificially with polyubiquitin chains and blocks their interactions with receptors on the proteasome. This opens up a new area in which a non-traditional target may be employed to inhibit protein turnover, although how this type of inhibitor could achieve specificity is not clear at present.

Abstract

Regulated protein turnover via the ubiquitin–proteasome system (UPS) underlies a wide variety of signalling pathways, from cell-cycle control and transcription to development. Recent evidence that pharmacological inhibition of the proteasome can be efficacious in the treatment of human cancers has set the stage for attempts to selectively inhibit the activities of disease-specific components of the UPS. Here, we review recent advances linking UPS components with specific human diseases, most prominently cancer and neurodegenerative disorders, and emphasize potential sites of therapeutic intervention along the regulated protein-degradation pathway.

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Figure 1: Overview of the ubiquitin–proteasome system (UPS).
Figure 2: Biochemical steps in the ubiquitin-activation reaction.
Figure 3: Ubiquitin-activating enzymes as potential pharmacological targets.
Figure 4: Ubiquitin ligases as ubiquitylation specificity modules.
Figure 5: RING-finger domain.
Figure 6: p53–MDM2 interaction as a therapeutic target in human cancer.
Figure 7: Recognition of phosphorylated substrates by SCF ubiquitin ligases.
Figure 8: Structure of HECT-domain ubiquitin ligases.

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Acknowledgements

Research on the ubiquitin pathway in the Harper laboratory is supported by the National Institutes of Health Grants.

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Correspondence to J. Wade Harper.

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M.R. is an employee of and owns stocks in Millennium Pharmaceuticals, Inc. J.W.H. is a consultant for Millennium Pharmaceuticals, Inc.

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DATABASES

OMIM

Angelman's syndrome

chronic myelogenous leukaemia

multiple myeloma

non-Hodgkin's lymphoma

Parkinson's disease

von Hippel-Lindau syndrome

Glossary

Neddylation

Covalent attachment of the ubiquitin-like protein NEDD8 (RUB1) to another protein.

Endoreduplication

Duplication of the genome without mitosis, which results in an increase in the nuclear DNA content, permitting amplification of the genome of specialized cells.

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Nalepa, G., Rolfe, M. & Harper, J. Drug discovery in the ubiquitin–proteasome system. Nat Rev Drug Discov 5, 596–613 (2006). https://doi.org/10.1038/nrd2056

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