3C7Q

Structure of VEGFR2 kinase domain in complex with BIBF1120

3C7Q の概要

• エントリーDOI: 10.2210/pdb3c7q/pdb
• 分子名称: Vascular endothelial growth factor receptor 2, SULFATE ION, methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate, ... (4 entities in total)
• 機能のキーワード: alpha beta, angiogenesis, atp-binding, developmental protein, differentiation, glycoprotein, host-virus interaction, immunoglobulin domain, kinase, membrane, nucleotide-binding, phosphoprotein, receptor, transferase, transmembrane, tyrosine-protein kinase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell junction . Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted . Isoform 3: Secreted: P35968
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37576.93

構造登録者

Hilberg, F.,Roth, G.J.,Krssak, M.,Kautschitsch, S.,Sommergruber, W.,Tontsch-Grunt, U.,Garin-Chesa, P.,Bader, G.,Zoephel, A.,Quant, J.,Heckel, A.,Rettig, W.J. (登録日: 2008-02-08, 公開日: 2008-12-23, 最終更新日: 2024-10-30)

主引用文献

Hilberg, F.,Roth, G.J.,Krssak, M.,Kautschitsch, S.,Sommergruber, W.,Tontsch-Grunt, U.,Garin-Chesa, P.,Bader, G.,Zoephel, A.,Quant, J.,Heckel, A.,Rettig, W.J.
BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.
Cancer Res., 68:4774-4782, 2008

PubMed Abstract: Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.

PubMed: 18559524
DOI: 10.1158/0008-5472.CAN-07-6307

実験手法

X-RAY DIFFRACTION (2.1 Å)