|Title||Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Herbert, C., U. Schieborr, K. Saxena, J. Juraszek, F. De Smet, C. Alcouffe, M. Bianciotto, G. Saladino, D. Sibrac, D. Kudlinzki, S. Sreeramulu, A. Brown, P. Rigon, J-P. Herault, G. Lassalle, T. L. Blundell, F. Rousseau, A. Gils, J. Schymkowitz, P. Tompa, J-M. Herbert, P. Carmeliet, F. Luigi Gervasio, H. Schwalbe, and F. Bono|
|Date Published||2013 Apr 15|
|Keywords||Allosteric 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|
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.
|Alternate Journal||Cancer Cell|