Abstract
Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.
2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Amines / chemistry*
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Aminopyridines / chemical synthesis*
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Aminopyridines / chemistry
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Aminopyridines / pharmacology
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Binding Sites
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Design
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Humans
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / metabolism
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Amines
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Aminopyridines
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-met