Kammasud Naparat, Boonyarat Chantana, Tsunoda Satoshi, Sakurai Hiroaki, Saiki Ikuo, Grierson David S, Vajragupta Opa
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Bioorg Med Chem Lett. 2007 Sep 1;17(17):4812-8. doi: 10.1016/j.bmcl.2007.06.058. Epub 2007 Jun 26.
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.
NP603，即6-二甲氧基苯基吲哚啉-2-酮，通过计算机研究被设计为成纤维细胞生长因子受体1（FGF receptor 1）抑制剂。NP603被合成出来，并且发现在rhFGF-2刺激后，它对人脐静脉内皮细胞（HUVEC）的内皮增殖活性比SU6668更高，最小有效剂量为0.4微摩尔，但效力与SU16g相似。NP603在rhFGF-2刺激后抑制了FGF受体中的酪氨酸磷酸化以及细胞外信号调节激酶和c-Jun氨基末端激酶的激活。NP603活性的增加支持了建模研究中Lys514移动在配体-受体结合中的作用，因为该移动适应了受体口袋处的疏水相互作用，从而导致结合能力增强。
