title: Targeting ubiquitin specific proteases for drug discovery.
abstract: Deregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of many human diseases, including cancer, neurodegenerative disorders and viral diseases. The recent approval of the proteasome inhibitor bortezomib (Velcade) for the treatment of multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to interact at the level of the upstream, ubiquitin conjugation/deconjugation system to generate more specific, less toxic anticancer agents. Ubiquitin specific proteases (USP) are de-ubiquitinating enzymes which remove ubiquitin from specific protein substrates and allow protein salvage from proteasome degradation, regulation of protein localization or activation. Due to their protease activity and their involvement in several pathologies, USPs are emerging as potential target sites for pharmacological interference in the ubiquitin regulatory machinery. We will review here this class of enzymes from target validation to small molecule drug discovery.
authors.affiliation: Hybrigenics SA, 3-5 Impasse Reille, 75014 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Daviet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Colland
mesh_terms: D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D064570:Ubiquitin-Specific Proteases; D014777:Virus Diseases / Q000188:drug therapy
chemical_list: D015853:Cysteine Proteinase Inhibitors; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases