GSK-3-selective inhibitors derived from Tyrian purple indirubins.
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.
Meijer
Laurent
L
CNRS, Cell Cycle Group, Station Biologique, BP 74, 29682 Roscoff cedex, Bretagne, France. meijer@sb-roscoff.fr
Skaltsounis
Alexios-Leandros
AL
Magiatis
Prokopios
P
Polychronopoulos
Panagiotis
P
Knockaert
Marie
M
Leost
Maryse
M
Ryan
Xiaozhou P
XP
Vonica
Claudia Alin
CA
Brivanlou
Ali
A
Dajani
Rana
R
Crovace
Claudia
C
Tarricone
Cataldo
C
Musacchio
Andrea
A
Roe
S Mark
SM
Pearl
Laurence
L
Greengard
Paul
P
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
D004791:Enzyme Inhibitors; D007211:Indoles; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D038362:Glycogen Synthase Kinase 3; C027185:indirubin