title: Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3.
abstract: In an effort to identify new protein kinase inhibitors with increased potency and selectivity, we have developed the microwave-assisted synthesis of thiazolo[5,4-f]quinazolin-9-ones. The effects of eighteen derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3 were investigated. Several turned out to inhibit GSK-3 in the micromolar range. Molecular modeling studies suggest that the most selective GSK-3 inhibitors 7a-d bind into the ATP-binding site through a key hydrogen bond interaction with Val135 and target the specific hydrophobic backpocket of the enzyme.
authors.affiliation: Laboratoire de Biotechnologies et de Chimie Bio-organique, FRE CNRS 2766, UFR Sciences Fondamentales et Sciences pour l'Ingénieur, Université de La Rochelle, Bâtiment Marie Curie, 17042 La Rochelle, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Testard
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.forename: Benoît
authors.initials: B
authors.lastname: Léger
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Robert
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Mélina
authors.initials: M
authors.lastname: Blairvacq
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Valérie
authors.initials: V
authors.lastname: Thiéry
authors.forename: Thierry
authors.initials: T
authors.lastname: Besson
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D008872:Microwaves; D008958:Models, Molecular; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D013844:Thiazoles; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3