Abstract
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Cell Division / drug effects
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Cell Line, Tumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Humans
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Inhibitory Concentration 50
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MAP Kinase Kinase 1
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Mice
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
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Neoplasms, Experimental / drug therapy
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Nitriles / chemical synthesis*
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Nitriles / pharmacology
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Quinolines / chemical synthesis
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Quinolines / pharmacology
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Transplantation, Heterologous
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Treatment Outcome
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Nitriles
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Quinolines
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Map2k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases