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A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2011 Nov; Vol. 10 (11), pp. 2200-10. Date of Electronic Publication: 2011 Sep 07. - Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents therapeutic use
Binding Sites
Blood Pressure drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Female
Humans
Indazoles chemistry
Indazoles therapeutic use
Male
Mice
Mice, Nude
Models, Molecular
Neoplasms drug therapy
Neoplasms metabolism
Phosphorylation drug effects
Protein Binding
Rats
Rats, Sprague-Dawley
Receptors, Fibroblast Growth Factor chemistry
Signal Transduction drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Indazoles pharmacology
Receptors, Fibroblast Growth Factor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 10
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 21900693
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-11-0306