Abstract
Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
MeSH terms
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Administration, Oral
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Animals
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Binding Sites
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Biological Availability
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In Vitro Techniques
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Mice
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Microsomes, Liver / metabolism
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Models, Molecular
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Oxazolidinones / chemical synthesis*
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Oxazolidinones / pharmacokinetics
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Oxazolidinones / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Tankyrases / antagonists & inhibitors*
Substances
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1-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohexyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo(d)imidazole-5-carbonitrile
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1-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohexyl)-6-fluoro-2-oxo-2,3-dihydro-1H-benzo(d)imidazole-5-carbonitrile
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Benzimidazoles
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Oxazolidinones
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Tankyrases
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Tnks protein, mouse