Abstract
Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Humans
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Inhibitory Concentration 50
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Male
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver / metabolism
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Phosphotransferases / antagonists & inhibitors*
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met
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Pyridones / chemical synthesis
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Pyridones / pharmacology*
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Receptors, Growth Factor / antagonists & inhibitors*
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Structure-Activity Relationship
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyridones
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Receptors, Growth Factor
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2-hydroxypyridine
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Phosphotransferases
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MET protein, human
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Proto-Oncogene Proteins c-met
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Vascular Endothelial Growth Factor Receptor-2
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fms-Like Tyrosine Kinase 3