Targeting Deubiquitinases in Cancer.

The ubiquitin-proteasome system (UPS) is a complex and robust metabolic pathway that contributes to the regulation of many key cellular processes including the cell cycle, cell division, and response to external stimuli. Ubiquitin ligases, which tag proteins with ubiquitin, are opposed by deubiquitinase enzymes (DUBs). The relative activity of these enzymes allows for a dynamic balance that determines the abundance and activity of cellular proteins. Targeting the UPS in cancer has proven successful, as evidenced by use of bortezomib, a proteasome inhibitor, in multiple myeloma. However, no pharmacologic inhibitor of the upstream enzymes has yet to reach clinical trials for the treatment of malignancy. Here we present an in vitro DUB assay for use in drug discovery and development that provides a biologically relevant platform for screening and developing lead or tool compounds targeting DUBs.