Abstract
Xylocydine (4-amino-6-bromo-7-(beta-l-xylofuranosyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide) blocks cyclin-dependent kinase CDK1 and CDK2/cyclin A activity in vitro (IC(50) 1.4 and 61 nM, respectively) while minimally inhibiting the three other Ser/Thr protein kinases tested (IC(50) 21-86 microM). Reduced phosphorylated nucleolin and retinoblastoma protein levels showed it also efficiently inhibited cellular CDK1 and CDK2 activity (IC(50) 50-100 and 200-500 nM, respectively). Moreover, it blocked the functional activity of CDKs in tumor necrosis factor-related apoptosis-inducing ligand-induced SK-HEP-1 cell apoptosis 20 to 1000-fold more potently than olomoucine and roscovitine. Xylocydine is thus a novel and potent CDK inhibitor that could be used to interfere with cell cycle- and apoptosis-related CDK activity in various diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins
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Apoptosis*
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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2-CDC28 Kinases / antagonists & inhibitors
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Cell Line
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cytidine / analogs & derivatives*
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Cytidine / pharmacology*
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Drug Interactions
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Enzyme Inhibitors / pharmacology*
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Humans
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Ligands
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Membrane Glycoproteins / pharmacology
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Apoptosis Regulatory Proteins
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Enzyme Inhibitors
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Ligands
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Membrane Glycoproteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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xylocytidine
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Cytidine
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CDC2 Protein Kinase
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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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Cyclin-Dependent Kinases