title: Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy.
abstract: Inhibition of the proteasome (a highly abundant enzymatic complex responsible for intracellular protein turnover) is an effective anti-cancer therapeutic approach, as demonstrated by the first-in-class agent bortezomib. Various new proteasome inhibitors are now in development, including peptide boronic acid analogs MLN9708 and CEP-18770, peptide epoxyketones carfilzomib and PR-047, and NPI-0052, a beta-lactone compound. All are potent inhibitors of proteasome activity in vitro but show differences in enzyme binding kinetics, which might affect their pharmacology and result in different efficacy and safety profiles. Here, we review the second-generation proteasome inhibitors and assess the potential pharmacologic impact of their different chemical properties.
authors.affiliation: Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA. Larry.Dick@mpi.com
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Dick
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fleming
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D001897:Boronic Acids / Q000737:chemistry* / Q000627:therapeutic use; D000069286:Bortezomib; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex