Deubiquitylating enzymes and drug discovery: emerging opportunities

Key Points

• The deubiquitylating enzyme (DUB) family contains ~100 proteins that remove the post-translational modification ubiquitin from a variety of substrates.

• DUBs have key roles in various areas of cell biology of high relevance to pathologies such as autoimmune disorders, chronic inflammation, oncology and neurodegeneration.

• DUBs are attractive targets for small-molecule drug discovery, as they contain a well-defined active site, and the majority of them have a catalytic cysteine.

• Oxidative hydrolysis of the active-site cysteine is a challenge for DUB inhibitor screening, as reducing agents are often required to maintain DUB activity but frequently result in high false-positive rates if used at high concentrations.

• Many of the reported DUB inhibitors have been shown to be rather non-selective in biochemical selectivity profiling assays.

• Recent advances in screening substrates and technologies, as well as activity-based probes for monitoring target engagement, have facilitated progress in DUB drug discovery.

• Increased understanding of DUB biology and emerging examples of potent and selective DUB inhibitors suggest that clinical development of DUB inhibitors is on the horizon.

Supplementary information

The online version of this article (doi:10.1038/nrd.2017.152) contains supplementary material, which is available to authorized users.

Abstract

Deubiquitylating enzymes (DUBs) have been implicated in several human diseases, including cancer, neurodegenerative diseases, inflammatory and autoimmune disorders, as well as infectious diseases. Here, Jackson and colleagues discuss the pathological roles of DUBs, consider the challenges in the development of selective DUB inhibitors and highlight first-generation agents approaching clinical trials.

Supplementary information

The online version of this article (doi:10.1038/nrd.2017.152) contains supplementary material, which is available to authorized users.

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.

Supplementary information

The online version of this article (doi:10.1038/nrd.2017.152) contains supplementary material, which is available to authorized users.