Abstract
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
MeSH terms
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Adenosine Triphosphate / metabolism
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Azepines / chemical synthesis*
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Azepines / chemistry
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Azepines / pharmacology*
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Binding Sites
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Cell Proliferation / drug effects
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Cells, Cultured
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ErbB Receptors / antagonists & inhibitors*
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Humans
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Molecular Structure
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Phosphorylation / drug effects
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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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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor, ErbB-2 / antagonists & inhibitors
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Azepines
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Protein Kinase Inhibitors
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Adenosine Triphosphate
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ErbB Receptors
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Protein-Tyrosine Kinases
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Receptor, ErbB-2
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Protein Serine-Threonine Kinases