5-Substituted pyrido[2,3- d]pyrimidine, an inhibitor against three receptor tyrosine kinases

• Published in: Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (3), p.745-750
• Main Authors: Kammasud, Naparat, Boonyarat, Chantana, Sanphanya, Kingkan, Utsintong, Maleeruk, Tsunoda, Satoshi, Sakurai, Hiroaki, Saiki, Ikuo, André, Isabelle, Grierson, David S., Vajragupta, Opa
• Format: Article
• Language: English
• Subjects: 5-Substituted indolin-2-one; Anti-angiogenesis; Anti-proliferation; Binding mode; Biological and medical sciences; Cell Proliferation; Cells, Cultured; Chemistry, Pharmaceutical - methods; Docking; Drug Design; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; FGFR-1; FGFR-1 inhibitor; Fibroblast Growth Factor 2 - metabolism; Humans; Indoles - pharmacology; JNK Mitogen-Activated Protein Kinases - metabolism; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Pyrroles - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; SU6668; Tyrosine - chemistry; Virtual screening
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.12.023

The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3- d]pyrimidine scaffold in NP506 led to the inhibitory effect in two signaling pathway: 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. NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-( N′-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1 H-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 μM. 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.