Antitumor and antiangiogenic activities of BMS-690514, an inhibitor of human EGF and VEGF receptor kinase families
| Autor: | Benjamin J. Henley, Bala Krishnan, Amy Hammell, Daniel W. Kukral, John T. Hunt, Joseph Fargnoli, Brian E. Fink, Derek J. Norris, Francis Y.F. Lee, Chiang Yu, Tai Wai Wong, Christine Hilt, Gregory D. Vite, Harold Malone, Ashvinikumar V. Gavai, Craig R. Fairchild, Stuart Emanuel, Anne Lewin, Simone Oppenheimer |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Receptor ErbB-2 Mice Nude Angiogenesis Inhibitors Antineoplastic Agents Apoptosis Pharmacology Tropomyosin receptor kinase C Cell Line Mice Piperidines Neoplasms medicine Potency Animals Humans Pyrroles Epidermal growth factor receptor Receptor Cell Proliferation chemistry.chemical_classification Mice Inbred BALB C biology Neovascularization Pathologic Kinase Triazines Cancer Endothelial Cells medicine.disease Xenograft Model Antitumor Assays ErbB Receptors stomatognathic diseases Enzyme Receptors Vascular Endothelial Growth Factor Oncology chemistry Regional Blood Flow biology.protein Female Signal Transduction |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(12) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: The extensive involvement of the HER kinases in epithelial cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514. Experimental Design: The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI. Results: BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS-690514, which may contribute to its efficacy. Conclusions: By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature. Clin Cancer Res; 17(12); 4031–41. ©2011 AACR. |
| Databáze: | OpenAIRE |
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