Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases.

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.

• Authors: Fawn Qian, Stefan Engst, Kyoko Yamaguchi, Peiwen Yu, Kwang-Ai Won, Lillian Mock, Tracy Lou, Jenny Tan, Connie Li, Danny Tam, Julie Lougheed, F Michael Yakes, Frauke Bentzien, Wei Xu, Tal Zaks, Richard Wooster, Joel Greshock, Alison H Joly
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 20 Pg. 8009-16 (Oct 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19808973 (Publication Type: Journal Article)

Chemical References

• Anilides
• GSK 1363089
• Protein Kinase Inhibitors
• Quinolines
• Hepatocyte Growth Factor
• Proto-Oncogene Proteins c-met
• Receptors, Vascular Endothelial Growth Factor

Topics

• Anilides (pharmacology)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dermis (cytology, drug effects, metabolism)
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Fibroblasts (drug effects, metabolism)
• Hepatocyte Growth Factor (pharmacology)
• Humans
• Lung Neoplasms (blood supply, drug therapy, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasms, Experimental (blood supply, drug therapy, pathology)
• Neovascularization, Pathologic (prevention & control)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Quinolines (pharmacology)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
• Umbilical Veins (cytology, drug effects, metabolism)