Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3.
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.
Testard
Alexandra
A
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.
Logé
Cédric
C
Léger
Benoît
B
Robert
Jean-Michel
JM
Lozach
Olivier
O
Blairvacq
Mélina
M
Meijer
Laurent
L
Thiéry
Valérie
V
Besson
Thierry
T
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
D004791:Enzyme Inhibitors; D011799:Quinazolines; D013844:Thiazoles; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3