Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule, Allosteric Inhibitor of FGF Receptor Signaling

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...

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Veröffentlicht in:	Cancer cell 2013-04, Vol.23 (4), p.489-501
Hauptverfasser:	Herbert, Corentin, Schieborr, Ulrich, Saxena, Krishna, Juraszek, Jarek, De Smet, Frederik, Alcouffe, Chantal, Bianciotto, Marc, Saladino, Giorgio, Sibrac, David, Kudlinzki, Denis, Sreeramulu, Sridhar, Brown, Alan, Rigon, Patrice, Herault, Jean-Pascal, Lassalle, Gilbert, Blundell, Tom L., Rousseau, Frederic, Gils, Ann, Schymkowitz, Joost, Tompa, Peter, Herbert, Jean-Marc, Carmeliet, Peter, Gervasio, Francesco Luigi, Schwalbe, Harald, Bono, Françoise
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric Regulation - drug effects Binding, Competitive Cell Growth Processes - drug effects Human Umbilical Vein Endothelial Cells - cytology Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Humans Phosphorylation - drug effects Protein Binding - drug effects Protein Conformation - drug effects Protein Kinase Inhibitors - pharmacology Protein Structure, Tertiary Receptors, Fibroblast Growth Factor - antagonists & inhibitors Receptors, Fibroblast Growth Factor - metabolism Signal Transduction - drug effects Small Molecule Libraries - pharmacology Structure-Activity Relationship
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Zusammenfassung:	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. ► SSR is an extracellular-binding, small-molecule, allosteric inhibitor of FGFRs ► SSR induces a conformational change in the extracellular FGFR domain ► SSR inhibits FGF-induced signaling linked to receptor internalization ► Biophysics and molecular modeling provide a model for SSR’s allosteric activity
ISSN:	1535-6108 1878-3686
DOI:	10.1016/j.ccr.2013.02.018