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

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• 作者：Corentin Herbert¹ ; ¹¹ ; Ulrich Schieborr² ; ¹¹ ; Krishna Saxena² ; ¹¹ ; Jarek Juraszek³ ; ¹¹ ; Frederik De Smet⁴ ; ⁵ ; ¹¹ ; Chantal Alcouffe¹ ; Marc Bianciotto¹ ; Giorgio Saladino³ ; David Sibrac¹ ; Denis Kudlinzki² ; Sridhar Sreeramulu² ; Alan Brown⁷ ; Patrice Rigon¹ ; Jean-Pascal Herault¹ ; Gilbert Lassalle¹ ; Tom L. Blundell⁷ ; Frederic Rousseau⁸ ; Ann Gils⁶ ; Joost Schymkowitz⁸ ; Peter Tompa⁹ ; ¹⁰ ; Jean-Marc Herbert¹ ; Peter Carmeliet⁴ ; ⁵ ; ¹¹ ; Francesco Luigi Gervasio³ ; ¹¹ ; ^{flgervasio@cnio.es} ; Harald Schwalbe² ; ¹¹ ; ^{schwalbe@nmr.uni-frankfurt.de} ; Franç ; oise Bono¹ ; ¹¹ ; ^{francoise.bono@sanofi-aventis.com}
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：15 April, 2013
• 年：2013
• 卷：23
• 期：4
• 页码：489-501
• 全文大小：2039 K

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Summary

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.