Abstract
Cyclin-dependent kinases (CDKs) are essential in the control of cell cycle progression. Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases, especially cancer. Based on the crystal structure of CDK2 in complex with an imidazole indolinone compound 1 (SU9516), lead optimization through modeling, synthesis, and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent CDK2 inhibitors.
MeSH terms
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Adenosine Triphosphate / metabolism
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Binding Sites
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CDC2-CDC28 Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinase 2
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Drug Design
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Indoles / chemistry*
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Lactams / chemistry*
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Lactams / pharmacology
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Lactones / chemistry*
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Lactones / pharmacology
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Models, Molecular
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Imidazoles
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Indoles
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Lactams
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Lactones
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imidazole
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Adenosine Triphosphate
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CDC2-CDC28 Kinases
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Cyclin-Dependent Kinase 2