title: Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.
abstract: Paullones constitute a new family of benzazepinones with promising antitumoral properties. They were recently described as potent, ATP-competitive, inhibitors of the cell cycle regulating cyclin-dependent kinases (CDKs). We here report that paullones also act as very potent inhibitors of glycogen synthase kinase-3beta (GSK-3beta) (IC50: 4-80 nM) and the neuronal CDK5/p25 (IC50: 20-200 nM). These two enzymes are responsible for most of the hyperphosphorylation of the microtubule-binding protein tau, a feature observed in the brains of patients with Alzheimer's disease and other neurodegenerative 'taupathies'. Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders.
authors.affiliation: CNRS, Cell Cycle Group, Station Biologique, Roscoff, Bretagne, France.
authors.forename: M
authors.initials: M
authors.lastname: Leost
authors.forename: C
authors.initials: C
authors.lastname: Schultz
authors.forename: A
authors.initials: A
authors.lastname: Link
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Wu
authors.forename: J
authors.initials: J
authors.lastname: Biernat
authors.forename: E M
authors.initials: EM
authors.lastname: Mandelkow
authors.forename: J A
authors.initials: JA
authors.lastname: Bibb
authors.forename: G L
authors.initials: GL
authors.lastname: Snyder
authors.forename: P
authors.initials: P
authors.lastname: Greengard
authors.forename: D W
authors.initials: DW
authors.lastname: Zaharevitz
authors.forename: R
authors.initials: R
authors.lastname: Gussio
authors.forename: A M
authors.initials: AM
authors.lastname: Senderowicz
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: C
authors.initials: C
authors.lastname: Kunick
authors.forename: L
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005822:Genetic Vectors / Q000235:genetics; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006131:Growth Inhibitors / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017924:Nucleopolyhedroviruses / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018411:Spodoptera / Q000166:cytology; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001552:Benzazepines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D016875:tau Proteins; D000255:Adenosine Triphosphate; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3