Developing DUB Inhibitors

DUBs have emerged as promising therapeutic targets. Misfolded proteins, which are common to many neurological disorders, can be eliminated from the cell by inhibiting DUBs. DUB inhibitors have also proven effective at overcoming resistance to widely used anticancer drugs such as cisplatin and bortezomib. Despite these advances, none of these inhibitors have advanced to the clinic due to weak potency and poor selectivity — two problems that plague many cysteine and metallo-proteases. Thus, knowledge of how DUBs target specific substrates is vital for guiding drug discovery efforts. Our ability to construct large quantities of well-defined ubiquitin chains puts us in a unique position to address this problem.