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Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880 (XL880, GSK1363089), a Novel Inhibitor of HGF and VEGF Receptor Tyrosine Kinases
Published version of a preprint
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 β, 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. [Cancer Res 2009;69(20):8009–16]
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“Crystal structures of foretinib in complex with three different kinases have been solved to date (c-Met, EphA2, and STK10) 64, 65”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [64]
Citations
Cites
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Active and Inactive Protein Kinases: Structural Basis for Regulation
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Yakes, F. M., Chen, J., Tan, J., Yamaguchi, T., Shi, Y., Yu, P., Qian, F., Chu, F., Bentzien, F., Cancilla, B., et al. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0264 · Cited by 1,350
Self-citationActivation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., LaFramboise, T., Abdel-Rahman, M., Wang, X., Levine, A. D., Rho, J. K., et al. (2012) · Nature Genetics · doi:10.1038/ng.2330 · Cited by 1,224
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Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923
Metadata
- Authors
- 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.
- Affiliations
- Exelixis (United States) (US)
- 1Exelixis, Inc., South San Francisco, California and
- GlaxoSmithKline (United States) (US)
- Venue
- Cancer Research
- Published
- 2009-10-14
- Volume
- 69
- Issue
- 20
- Pages
- 8009-8016
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2130921495
- Cited by
- 350
- References
- 48
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 18 · 2023: 24 · 2022: 14 · 2021: 25 · 2020: 20 · 2019: 12 · 2018: 13 · 2017: 26 · 2016: 17 · 2015: 31 · 2014: 20 · 2013: 44 · 2012: 27
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- MET receptor tyrosine kinase, hepatocyte growth factor, tyrosine kinase inhibitors, tumor invasion, lung metastasis, angiogenesis, tumor cell proliferation, hypoxia, endothelial cells, KIT, FLT3, PDGFRβ, Tie2
- MeSH terms
- Anilides, Animals, Cell Adhesion, Cell Movement, Cells, Cultured, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Female, Fibroblasts, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Neoplasm Invasiveness, Neoplasms, Experimental, Neovascularization, Pathologic, Phosphorylation, Quinolines, Umbilical Veins, Blotting, Western, Apoptosis, Hepatocyte Growth Factor, Proto-Oncogene Proteins c-met, Dermis, Receptors, Vascular Endothelial Growth Factor, Protein Kinase Inhibitors, Cell Proliferation, Mice
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