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

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.

• Authors: Françoise Bono, Frederik De Smet, Corentin Herbert, Katrien De Bock, Maria Georgiadou, Pierre Fons, Marc Tjwa, Chantal Alcouffe, Annelii Ny, Marc Bianciotto, Bart Jonckx, Masahiro Murakami, Anthony A Lanahan, Christof Michielsen, David Sibrac, Frédérique Dol-Gleizes, Massimiliano Mazzone, Serena Zacchigna, Jean-Pascal Herault, Christian Fischer, Patrice Rigon, Carmen Ruiz de Almodovar, Filip Claes, Isabelle Blanc, Koen Poesen, Jie Zhang, Inmaculada Segura, Geneviève Gueguen, Marie-Françoise Bordes, Diether Lambrechts, Roselyne Broussy, Marlies van de Wouwer, Corinne Michaux, Toru Shimada, Isabelle Jean, Silvia Blacher, Agnès Noel, Patrick Motte, Eran Rom, Jean-Marie Rakic, Susumu Katsuma, Paul Schaeffer, Avner Yayon, Ann Van Schepdael, Harald Schwalbe, Francesco Luigi Gervasio, Geert Carmeliet, Jef Rozensky, Mieke Dewerchin, Michael Simons, Arthur Christopoulos, Jean-Marc Herbert, Peter Carmeliet
• Journal: Cancer cell (Cancer Cell) Vol. 23 Issue 4 Pg. 477-88 (Apr 15 2013) ISSN: 1878-3686 [Electronic] United States
• PMID: 23597562 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• DC101 monoclonal antibody
• Protein Kinase Inhibitors
• Receptors, Fibroblast Growth Factor
• Small Molecule Libraries
• Fibroblast Growth Factors
• Receptor Protein-Tyrosine Kinases

Topics

• Allosteric Regulation
• Animals
• Antibodies, Monoclonal (pharmacology)
• Arthritis, Experimental (drug therapy)
• Bone Resorption (drug therapy)
• Carcinoma, Lewis Lung (drug therapy, metabolism, pathology)
• Fibroblast Growth Factors (antagonists & inhibitors, metabolism)
• HEK293 Cells
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Mice
• Neovascularization, Pathologic (drug therapy)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (metabolism, pharmacology)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, metabolism)
• Signal Transduction
• Small Molecule Libraries (pharmacology)
• Xenograft Model Antitumor Assays