Potent, selective inhibitors of fibroblast growth factor receptor define fibroblast growth factor dependence in preclinical cancer models.

Abstract

We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.

• Authors: Matthew Squires, George Ward, Gordan Saxty, Valerio Berdini, Anne Cleasby, Peter King, Patrick Angibaud, Tim Perera, Lynsey Fazal, Douglas Ross, Charlotte Griffiths Jones, Andrew Madin, Rajdeep K Benning, Emma Vickerstaffe, Alistair O'Brien, Martyn Frederickson, Michael Reader, Christopher Hamlett, Michael A Batey, Sharna Rich, Maria Carr, Darcey Miller, Ruth Feltell, Abarna Thiru, Susanne Bethell, Lindsay A Devine, Brent L Graham, Andrew Pike, Jose Cosme, Edward J Lewis, Eddy Freyne, John Lyons, Julie Irving, Christopher Murray, David R Newell, Neil T Thompson
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 9 Pg. 1542-52 (Sep 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21764904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Receptors, Fibroblast Growth Factor
• Fibroblast Growth Factors

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Design
• Drug Evaluation, Preclinical
• Fibroblast Growth Factors (metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Neoplasms (drug therapy, metabolism)
• Protein Kinase Inhibitors (chemistry, pharmacology, therapeutic use)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Treatment Outcome
• Xenograft Model Antitumor Assays