Abstract
A novel class of 3,5,6-trisubstituted naphthostyril analogues was designed and synthesized to study the structure-activity relationship for inhibition of cyclin-dependent kinase 2 (CDK2). These compounds, particularly molecules with side-chain modifications providing additional hydrogen bonding capability, were demonstrated to be potent CDK2 inhibitors with cellular activities consistent with CDK2 inhibition. These molecules inhibited tumor cell proliferation and G1-S and G2-M cell-cycle progression in vitro. The X-ray crystal structure of a 2-aminoethyleneamine derivative bound to CDK2, refined to 2.5A resolution, is presented.
MeSH terms
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Antimetabolites
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Bromodeoxyuridine
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CDC2-CDC28 Kinases / antagonists & inhibitors*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Crystallography, X-Ray
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Cyclin-Dependent Kinase 2
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Humans
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Indicators and Reagents
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Models, Molecular
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Molecular Conformation
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Naphthalenes / chemical synthesis*
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Naphthalenes / pharmacology*
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Oxidation-Reduction
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacology*
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Tetrazolium Salts
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Thiazoles
Substances
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Antimetabolites
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Enzyme Inhibitors
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Indicators and Reagents
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Naphthalenes
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Pyrroles
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Tetrazolium Salts
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Thiazoles
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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thiazolyl blue
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Bromodeoxyuridine