Abstract
Using structure-based design, two novel series of highly potent biaryl amine mitogen-activated protein kinase kinase (MEK) inhibitors have been discovered. These series contain an H-bond acceptor, in a shifted position compared with previously disclosed compounds, and an adjacent H-bond donor, resulting in a bidentate interaction with the Ser212 residue of MEK1. The most potent compound identified, 1 (G-894), is orally active in in vivo pharmacodynamic and tumor xenograft models.
MeSH terms
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Allosteric Regulation
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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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Benzofurans / chemical synthesis*
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Benzofurans / pharmacokinetics
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Benzofurans / pharmacology
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Benzothiazoles / chemical synthesis*
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Benzothiazoles / pharmacokinetics
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Benzothiazoles / 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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Drug Screening Assays, Antitumor
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Female
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Hydrogen Bonding
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Indazoles / chemical synthesis*
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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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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Models, Molecular
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Molecular Structure
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Neoplasm Transplantation
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Rats
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Serine / metabolism*
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (2-hydroxyethoxy)amide
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Antineoplastic Agents
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Benzofurans
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Benzothiazoles
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Indazoles
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Serine
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2