Abstract
NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N'-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 microM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3'-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Proliferation
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Cells, Cultured
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Chemistry, Pharmaceutical / methods*
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Drug Design
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Fibroblast Growth Factor 2 / metabolism
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Humans
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Indoles / pharmacology
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JNK Mitogen-Activated Protein Kinases / metabolism
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Oxindoles
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Phosphorylation
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Propionates
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology*
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Pyrroles / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Tyrosine / chemistry
Substances
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Enzyme Inhibitors
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Indoles
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Oxindoles
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Propionates
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Pyrimidines
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Pyrroles
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Fibroblast Growth Factor 2
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Tyrosine
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orantinib
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Receptor Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases