Abstract
A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.
MeSH terms
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Animals
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Aurora Kinase B
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Aurora Kinases
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Cell Cycle / drug effects
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / pathology
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Cytochrome P-450 CYP3A / metabolism
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Electrophysiology
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Ether-A-Go-Go Potassium Channels / metabolism
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Histones / metabolism
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Humans
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Male
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Mice
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Mice, Nude
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Molecular Structure
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrazoles / chemistry*
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Quinazolines / chemical synthesis*
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Rats
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Rats, Wistar
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Ether-A-Go-Go Potassium Channels
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Histones
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KCNH1 protein, human
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Protein Kinase Inhibitors
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Pyrazoles
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Quinazolines
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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AURKB protein, human
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Aurkb protein, mouse
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Aurkb protein, rat
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases