3LQ8

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

Summary for 3LQ8

• Entry DOI: 10.2210/pdb3lq8/pdb
• Descriptor: 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)
• Functional Keywords: kinase domain, xl880, gsk1363089, atp-binding, kinase, nucleotide-binding, phosphoprotein, proto-oncogene, receptor, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P08581
• Total number of polymer chains: 1
• Total formula weight: 34834.28

Authors

Lougheed, J.C.,Stout, T.J. (deposition date: 2010-02-08, release date: 2010-05-19, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.02 Å)