5-Substituted pyrido[2,3-d]pyrimidine, an inhibitor against three receptor tyrosine kinases.
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.
Kammasud
Naparat
N
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand.
Boonyarat
Chantana
C
Sanphanya
Kingkan
K
Utsintong
Maleeruk
M
Tsunoda
Satoshi
S
Sakurai
Hiroaki
H
Saiki
Ikuo
I
André
Isabelle
I
Grierson
David S
DS
Vajragupta
Opa
O
D049109:Cell Proliferation; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000078183:Oxindoles; D010766:Phosphorylation; D011422:Propionates; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000737:chemistry
D004791:Enzyme Inhibitors; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011743:Pyrimidines; D011758:Pyrroles; D016222:Fibroblast Growth Factor 2; D014443:Tyrosine; C412603:orantinib; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases