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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / chemistry
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Binding Sites
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Crystallography, X-Ray
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / radiation effects
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Hydrogen Bonding
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Microwaves
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Models, Molecular
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Quinazolines / radiation effects
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Stereoisomerism
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Structure-Activity Relationship
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Thiazoles / chemistry
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Thiazoles / pharmacology*
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Thiazoles / radiation effects
Substances
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Enzyme Inhibitors
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Quinazolines
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Thiazoles
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Adenosine Triphosphate
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Cyclin-Dependent Kinases
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Glycogen Synthase Kinase 3