title: GSK-3-selective inhibitors derived from Tyrian purple indirubins.
abstract: Gastropod mollusks have been used for over 2500 years to produce the "Tyrian purple" dye made famous by the Phoenicians. This dye is constituted of mixed bromine-substituted indigo and indirubin isomers. Among these, the new natural product 6-bromoindirubin and its synthetic, cell-permeable derivative, 6-bromoindirubin-3'-oxime (BIO), display remarkable selective inhibition of glycogen synthase kinase-3 (GSK-3). Cocrystal structure of GSK-3beta/BIO and CDK5/p25/indirubin-3'-oxime were resolved, providing a detailed view of indirubins' interactions within the ATP binding pocket of these kinases. BIO but not 1-methyl-BIO, its kinase inactive analog, also inhibited the phosphorylation on Tyr276/216, a GSK-3alpha/beta activation site. BIO but not 1-methyl-BIO reduced beta-catenin phosphorylation on a GSK-3-specific site in cellular models. BIO but not 1-methyl-BIO closely mimicked Wnt signaling in Xenopus embryos. 6-bromoindirubins thus provide a new scaffold for the development of selective and potent pharmacological inhibitors of GSK-3.
authors.affiliation: CNRS, Cell Cycle Group, Station Biologique, BP 74, 29682 Roscoff cedex, Bretagne, France. meijer@sb-roscoff.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.forename: Prokopios
authors.initials: P
authors.lastname: Magiatis
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Polychronopoulos
authors.forename: Marie
authors.initials: M
authors.lastname: Knockaert
authors.forename: Maryse
authors.initials: M
authors.lastname: Leost
authors.forename: Xiaozhou P
authors.initials: XP
authors.lastname: Ryan
authors.forename: Claudia Alin
authors.initials: CA
authors.lastname: Vonica
authors.forename: Ali
authors.initials: A
authors.lastname: Brivanlou
authors.forename: Rana
authors.initials: R
authors.lastname: Dajani
authors.forename: Claudia
authors.initials: C
authors.lastname: Crovace
authors.forename: Cataldo
authors.initials: C
authors.lastname: Tarricone
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Laurence
authors.initials: L
authors.lastname: Pearl
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012758:Shellfish; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D051153:Wnt Proteins; D014981:Xenopus / Q000196:embryology / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D038362:Glycogen Synthase Kinase 3; C027185:indirubin