Abstract
The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.
MeSH terms
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Animals
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Benzamides / pharmacology*
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Benzamides / therapeutic use
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Cadherins / analysis
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Cell Cycle / drug effects*
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Cell Division / 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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Colonic Neoplasms / physiopathology*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Female
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Hepatocyte Growth Factor / pharmacology
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Humans
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Male
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Mice
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Mice, Inbred Strains
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Mice, Nude
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Neoplasm Invasiveness / prevention & control
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Signal Transduction / drug effects*
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
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Benzamides
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Cadherins
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Enzyme Inhibitors
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Hepatocyte Growth Factor
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Calcium-Calmodulin-Dependent Protein Kinases