Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.

TitleMolecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.
Publication TypeJournal Article
Year of Publication2013
AuthorsHerbert, C., Schieborr U., Saxena K., Juraszek J., De Smet F., Alcouffe C., Bianciotto M., Saladino G., Sibrac D., Kudlinzki D., Sreeramulu S., Brown A., Rigon P., Herault J-P., Lassalle G., Blundell T. L., Rousseau F., Gils A., Schymkowitz J., Tompa P., Herbert J-M., Carmeliet P., Gervasio F. Luigi, Schwalbe H., and Bono F.
JournalCancer Cell
Volume23
Issue4
Pagination489-501
Date Published2013 Apr 15
ISSN1878-3686
KeywordsAllosteric Regulation, Binding, Competitive, Cell Growth Processes, Human Umbilical Vein Endothelial Cells, Humans, Phosphorylation, Protein Binding, Protein Conformation, Protein Kinase Inhibitors, Protein Structure, Tertiary, Receptors, Fibroblast Growth Factor, Signal Transduction, Small Molecule Libraries, Structure-Activity Relationship
Abstract

The fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling network plays an important role in cell growth, survival, differentiation, and angiogenesis. Deregulation of FGFR signaling can lead to cancer development. Here, we report an FGFR inhibitor, SSR128129E (SSR), that binds to the extracellular part of the receptor. SSR does not compete with FGF for binding to FGFR but inhibits FGF-induced signaling linked to FGFR internalization in an allosteric manner, as shown by crystallography studies, nuclear magnetic resonance, Fourier transform infrared spectroscopy, molecular dynamics simulations, free energy calculations, structure-activity relationship analysis, and FGFR mutagenesis. Overall, SSR is a small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR.

DOI10.1016/j.ccr.2013.02.018
Alternate JournalCancer Cell
PubMed ID23597563