Novel inhibitor for fibroblast growth factor receptor tyrosine kinase.
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.
Kammasud
Naparat
N
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Boonyarat
Chantana
C
Tsunoda
Satoshi
S
Sakurai
Hiroaki
H
Saiki
Ikuo
I
Grierson
David S
DS
Vajragupta
Opa
O
D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008956:Models, Chemical; D008968:Molecular Conformation; D000078183:Oxindoles; D011422:Propionates; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007211:Indoles; D000078183:Oxindoles; C115711:PD 173074; D011422:Propionates; D011743:Pyrimidines; D011758:Pyrroles; D016220:Fibroblast Growth Factor 1; C412603:orantinib; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048031:JNK Mitogen-Activated Protein Kinases; D008239:Lysine