title: Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib.
abstract: Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated.
authors.affiliation: Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA. mark.williamson@mpi.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Williamson
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Blank
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Bruzzese
authors.forename: Yueying
authors.initials: Y
authors.lastname: Cao
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Dick
authors.forename: Jason
authors.initials: J
authors.lastname: Labutti
authors.forename: Anne M
authors.initials: AM
authors.lastname: Mazzola
authors.forename: Ashok D
authors.initials: AD
authors.lastname: Patil
authors.forename: Corinne L
authors.initials: CL
authors.lastname: Reimer
authors.forename: Marjorie S
authors.initials: MS
authors.lastname: Solomon
authors.forename: Matthew
authors.initials: M
authors.lastname: Stirling
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Tsu
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Weatherhead
authors.forename: Julie X
authors.initials: JX
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Rolfe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D000069286:Bortezomib; D004355:Drug Stability; D005260:Female; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C475865:marizomib; D046988:Proteasome Endopeptidase Complex