title: Deubiquitinase inhibition as a cancer therapeutic strategy.
abstract: The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing α,β-unsaturated ketones have indeed been demonstrated to inhibit cellular DUB activity. Inhibition of proteasomal cysteine DUB enzymes (i.e. USP14 and UCHL5) can be predicted to be particularly cytotoxic to cancer cells as it leads to blocking of proteasome function and accumulation of proteasomal substrates. We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity.
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden; Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden; Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden; Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden. Electronic address: Stig.Linder@liu.se.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D064570:Ubiquitin-Specific Proteases
keywords: Apoptosis; Cancer therapeutics; Deubiquitinase; Proteasome; Small molecule inhibitors; α,β-unsaturated ketones