A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models
| Autor: | Karen L. Huss, Daohong Chen, Genshi Zhao, Sheng Bin Peng, Zhaogen Chen, Yan Zhai, Mohammad Zia-Ebrahimi, Wei Ying Li, Laura J. Bloem, Henry James Robert, Hongyu Li, Denis J. McCann |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Models Molecular Cancer Research Indazoles Mice Nude Antineoplastic Agents Blood Pressure Plasma protein binding Pharmacology Biology Fibroblast growth factor Rats Sprague-Dawley Mice In vivo Cell Line Tumor Neoplasms Animals Humans Phosphorylation Receptor Cell Proliferation Binding Sites Receptors Fibroblast Growth Factor Xenograft Model Antitumor Assays In vitro Rats Oncology Cell culture Fibroblast growth factor receptor Female Tyrosine kinase Protein Binding Signal Transduction |
| Zdroj: | Molecular cancer therapeutics. 10(11) |
| ISSN: | 1538-8514 |
| Popis: | The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells and play an important role in tumor cell growth, survival, and migration as well as in maintaining tumor angiogenesis. Overexpression of FGFRs or aberrant regulation of their activities has been implicated in many forms of human malignancies. Therefore, targeting FGFRs represents an attractive strategy for development of cancer treatment options by simultaneously inhibiting tumor cell growth, survival, and migration as well as tumor angiogenesis. Here, we describe a potent, selective, small-molecule FGFR inhibitor, (R)-(E)-2-(4-(2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol, designated as LY2874455. This molecule is active against all 4 FGFRs, with a similar potency in biochemical assays. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship. LY2874455 also exhibits a 6- to 9-fold in vitro and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice. Furthermore, LY2874455 did not show VEGF receptor 2–mediated toxicities such as hypertension at efficacious doses. Currently, this molecule is being evaluated for its potential use in the clinic. Mol Cancer Ther; 10(11); 2200–10. ©2011 AACR. |
| Databáze: | OpenAIRE |
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