Deubiquitylating enzymes and drug discovery: emerging opportunities

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.