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Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties

Item Type:Article
Title:Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties
Creators Name:Bono, F. and De Smet, F. and Herbert, C. and De Bock, K. and Georgiadou, M. and Fons, P. and Tjwa, M. and Alcouffe, C. and Ny, A. and Bianciotto, M. and Jonckx, B. and Murakami, M. and Lanahan, A.A. and Michielsen, C. and Sibrac, D. and Dol-Gleizes, F. and Mazzone, M. and Zacchigna, S. and Herault, J.P. and Fischer, C. and Rigon, P. and Ruiz de Almodovar, C. and Claes, F. and Blanc, I. and Poesen, K. and Zhang, J. and Segura, I. and Gueguen, G. and Bordes, M.F. and Lambrechts, D. and Broussy, R. and van de Wouwer, M. and Michaux, C. and Shimada, T. and Jean, I. and Blacher, S. and Noel, A. and Motte, P. and Rom, E. and Rakic, J.M. and Katsuma, S. and Schaeffer, P. and Yayon, A. and Van Schepdael, A. and Schwalbe, H. and Gervasio, F.L. and Carmeliet, G. and Rozensky, J. and Dewerchin, M. and Simons, M. and Christopoulos, A. and Herbert, J.M. and Carmeliet, P.
Abstract:Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.
Keywords:Allosteric Regulation, Bone Resorption, Experimental Arthritis, Fibroblast Growth Factor Receptors, Fibroblast Growth Factors, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Lewis Lung Carcinoma, Monoclonal Antibodies, Pancreatic Neoplasms, Pathologic Neovascularization, Phosphorylation, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Signal Transduction, Small Molecule Libraries, Xenograft Model Antitumor Assays, Animals, Mice
Source:Cancer Cell
ISSN:1535-6108
Publisher:Cell Press (U.S.A.)
Volume:23
Number:4
Page Range:477-488
Date:15 April 2013
Official Publication:https://doi.org/10.1016/j.ccr.2013.02.019
PubMed:View item in PubMed

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