1. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.
- Author
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Bono F, De Smet F, Herbert C, De Bock K, Georgiadou M, Fons P, Tjwa M, Alcouffe C, Ny A, Bianciotto M, Jonckx B, Murakami M, Lanahan AA, Michielsen C, Sibrac D, Dol-Gleizes F, Mazzone M, Zacchigna S, Herault JP, Fischer C, Rigon P, Ruiz de Almodovar C, Claes F, Blanc I, Poesen K, Zhang J, Segura I, Gueguen G, Bordes MF, Lambrechts D, Broussy R, van de Wouwer M, Michaux C, Shimada T, Jean I, Blacher S, Noel A, Motte P, Rom E, Rakic JM, Katsuma S, Schaeffer P, Yayon A, Van Schepdael A, Schwalbe H, Gervasio FL, Carmeliet G, Rozensky J, Dewerchin M, Simons M, Christopoulos A, Herbert JM, and Carmeliet P
- Subjects
- Allosteric Regulation, Animals, Antibodies, Monoclonal pharmacology, Arthritis, Experimental drug therapy, Bone Resorption drug therapy, Carcinoma, Lewis Lung drug therapy, Carcinoma, Lewis Lung metabolism, Carcinoma, Lewis Lung pathology, Fibroblast Growth Factors antagonists & inhibitors, Fibroblast Growth Factors metabolism, HEK293 Cells, Human Umbilical Vein Endothelial Cells cytology, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Humans, Mice, Neovascularization, Pathologic drug therapy, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Phosphorylation drug effects, Protein Kinase Inhibitors metabolism, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Signal Transduction, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors pharmacology, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Receptors, Fibroblast Growth Factor metabolism, Small Molecule Libraries pharmacology
- 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., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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