Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade.
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:
Animals, Antineoplastic Agents, Cell Division, Cell Line, Tumor, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, MAP Kinase Kinase 1, Mice, Mitogen-Activated Protein Kinase Kinases, Neoplasms, Experimental, Nitriles, Quinolines, Signal Transduction, Structure-Activity Relationship, Transplantation, Heterologous, Treatment Outcome
Animals, Antineoplastic Agents, Cell Division, Cell Line, Tumor, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, MAP Kinase Kinase 1, Mice, Mitogen-Activated Protein Kinase Kinases, Neoplasms, Experimental, Nitriles, Quinolines, Signal Transduction, Structure-Activity Relationship, Transplantation, Heterologous, Treatment Outcome
Bioorg Med Chem Lett
Date: Sep. 15, 2003
PubMed ID: 12941327
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