Abstract
A new class of Aurora A kinase inhibitor was created by transforming 4-(5-methyl-3-pyrazoloamino)pyrimidine moiety of VX-680 to 3-cyano-6-(5-methyl-3pyrazoloamino)pyridine. Compound 6 exhibited a potent Aurora A kinase inhibitory activity, excellent selectivity to Aurora B kinase and other 60 kinases, good cell permeability and good PK profile. Therefore compound 6 was effective in antitumor mice model at a dose of 30 mg/kg po qd without decrease of body weight.
Copyright 2010. Published by Elsevier Ltd.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Aurora Kinase A
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Aurora Kinase B
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Aurora Kinases
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Cell Line, Tumor
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Humans
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Mice
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Mice, Nude
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Piperazines / chemistry
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Rats
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Xenograft Model Antitumor Assays
Substances
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4-(5-methyl-3-pyrazoloamino)pyrimidine
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Antineoplastic Agents
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Piperazines
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridines
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Pyrimidines
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tozasertib
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AURKB protein, human
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Aurka protein, mouse
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Aurka protein, rat
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Aurkb protein, mouse
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Aurkb protein, rat
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Aurora Kinase A
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases