Discovery of Therapeutic Deubiquitylase Effector Molecules: Current Perspectives

The approval of proteasome inhibitors bortezomib and carfilzomib and the E3 ligase antagonist thalidomide and its analogs, lenalidomide and pomalidomide, validates the ubiquitin-proteasome pathway as a source of novel drugs for treating cancer and, potentially, a variety of devastating illnesses, including inflammation, cardiovascular disease, and neurodegenerative disease. All elements of this critical regulatory pathway-the proteasome itself, E3 ligases (which conjugate ubiquitin to target proteins), and deubiquitylating enzymes (which deconjugate ubiquitin, reversing ligase action)-are potential therapeutic targets, and all have been worked on extensively during the past decade. No deubiquitylase inhibitors or activators have yet progressed to clinical trial, however, despite compelling target validation and several years of high-throughput screening and preclinical development of hits by numerous pharmaceutical companies, biotechnology organizations, and academic groups. The appropriateness of deubiquitylases as therapeutic targets in many disease areas is reviewed, followed by evidence that selective inhibitors of these cysteine proteases can be discovered. Because the lack of progress in drug-discovery efforts with deubiquitylases suggests a need for improved discovery methodologies, currently available platforms and strategies are analyzed, and improved or completely novel, unrelated approaches are considered in terms of their likelihood of producing clinically viable effectors of deubiquitylases.