期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 19, 期 3, 页码 745-750出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.12.023
关键词
FGFR-1; FGFR-1 inhibitor; SU6668; 5-Substituted indolin-2-one; Virtual screening; Docking; Binding mode; Anti-proliferation; Anti-angiogenesis
资金
- Royal Golden Jubilee Project
- Thailand Research Fund
- Commission of Higher Education
- Ministry of Education, Thailand
- Ministry of Education, Culture, Sports, Science and Technology, Japan
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 mu M. 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 30-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway. (C) 2008 Elsevier Ltd. All rights reserved.
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