title: Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition.
abstract: Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Buck
authors.forename: Christophe
authors.initials: C
authors.lastname: Hardouin
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Soenen
authors.forename: C-M
authors.initials: CM
authors.lastname: Gauss
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Mark R
authors.initials: MR
authors.lastname: Swingle
authors.forename: Kathy M
authors.initials: KM
authors.lastname: Bonness
authors.forename: Richard E
authors.initials: RE
authors.lastname: Honkanen
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011090:Polyenes; D011753:Pyrones; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D004791:Enzyme Inhibitors; D007783:Lactones; D011090:Polyenes; D011753:Pyrones; D010749:Phosphoprotein Phosphatases; C040313:fostriecin