Abstract
NP603, the 6-dimethoxy phenyl indolin-2-one, was designed as FGF receptor 1 inhibitor by computational study. NP603 was synthesized and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 0.4 microM but with similar potency as SU16g. NP603 inhibited the tyrosine phosphorylation in FGF receptor and the activation of extracellular signal-regulated kinase and c-Jun-N-terminal-kinase after the rhFGF-2 stimulation. The increase in activity of NP603 supports the role of Lys514 movement in ligand-receptor binding in modeling study as the movement accommodates the hydrophobic interaction at the receptor pocket leading to the enhancement of binding capacity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Chemistry, Pharmaceutical / methods
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Design
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Fibroblast Growth Factor 1 / chemistry
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Humans
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Hydrogen Bonding
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Indoles / pharmacology
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lysine / chemistry
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Models, Chemical
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Molecular Conformation
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Oxindoles
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Propionates
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Pyrimidines / pharmacology
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Pyrroles / pharmacology
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Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
Substances
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Enzyme Inhibitors
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Indoles
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Oxindoles
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PD 173074
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Propionates
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Pyrimidines
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Pyrroles
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Fibroblast Growth Factor 1
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orantinib
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Receptor, Fibroblast Growth Factor, Type 1
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JNK Mitogen-Activated Protein Kinases
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Lysine