3LQ8

Structure of the kinase domain of c-Met bound to XL880 (GSK1363089)

3LQ8 の概要

• エントリーDOI: 10.2210/pdb3lq8/pdb
• 分子名称: Hepatocyte growth factor receptor, N-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3 entities in total)
• 機能のキーワード: kinase domain, xl880, gsk1363089, atp-binding, kinase, nucleotide-binding, phosphoprotein, proto-oncogene, receptor, transferase, transmembrane, tyrosine-protein kinase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P08581
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34834.28

構造登録者

Lougheed, J.C.,Stout, T.J. (登録日: 2010-02-08, 公開日: 2010-05-19, 最終更新日: 2024-04-03)

主引用文献

Qian, F.,Engst, S.,Yamaguchi, K.,Yu, P.,Won, K.A.,Mock, L.,Lou, T.,Tan, J.,Li, C.,Tam, D.,Lougheed, J.,Yakes, F.M.,Bentzien, F.,Xu, W.,Zaks, T.,Wooster, R.,Greshock, J.,Joly, A.H.
Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases.
Cancer Res., 69:8009-8016, 2009

PubMed Abstract: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor beta, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addition, EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.

PubMed: 19808973
DOI: 10.1158/0008-5472.CAN-08-4889

実験手法

X-RAY DIFFRACTION (2.02 Å)