Abstract
The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.
MeSH terms
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / pharmacokinetics
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Aniline Compounds / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line
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Cell Line, Tumor
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Cell Membrane Permeability
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Cell Survival / drug effects
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Drug Stability
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Hepatocytes / metabolism
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Humans
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In Vitro Techniques
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MAP Kinase Kinase 1 / antagonists & inhibitors*
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MAP Kinase Kinase 2 / antagonists & inhibitors*
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Mice
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Phosphorylation
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Solubility
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Aniline Compounds
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Antineoplastic Agents
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Pyridines
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2