title: Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.
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.
authors.affiliation: E2C and LGCR-SDI Department, Sanofi Research and Development, 31100 Toulouse, France.
authors.forename: Corentin
authors.initials: C
authors.lastname: Herbert
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schieborr
authors.forename: Krishna
authors.initials: K
authors.lastname: Saxena
authors.forename: Jarek
authors.initials: J
authors.lastname: Juraszek
authors.forename: Frederik
authors.initials: F
authors.lastname: De Smet
authors.forename: Chantal
authors.initials: C
authors.lastname: Alcouffe
authors.forename: Marc
authors.initials: M
authors.lastname: Bianciotto
authors.forename: Giorgio
authors.initials: G
authors.lastname: Saladino
authors.forename: David
authors.initials: D
authors.lastname: Sibrac
authors.forename: Denis
authors.initials: D
authors.lastname: Kudlinzki
authors.forename: Sridhar
authors.initials: S
authors.lastname: Sreeramulu
authors.forename: Alan
authors.initials: A
authors.lastname: Brown
authors.forename: Patrice
authors.initials: P
authors.lastname: Rigon
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Herault
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lassalle
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.forename: Peter
authors.initials: P
authors.lastname: Tompa
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Harald
authors.initials: H
authors.lastname: Schwalbe
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001667:Binding, Competitive; D048708:Cell Growth Processes / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D054852:Small Molecule Libraries