title: Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.
abstract: Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.
authors.affiliation: Early to Candidate Department and Lead Generation and Candidate Realization Department, Sanofi, 31036 Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
authors.forename: Frederik
authors.initials: F
authors.lastname: De Smet
authors.forename: Corentin
authors.initials: C
authors.lastname: Herbert
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.forename: Maria
authors.initials: M
authors.lastname: Georgiadou
authors.forename: Pierre
authors.initials: P
authors.lastname: Fons
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Chantal
authors.initials: C
authors.lastname: Alcouffe
authors.forename: Annelii
authors.initials: A
authors.lastname: Ny
authors.forename: Marc
authors.initials: M
authors.lastname: Bianciotto
authors.forename: Bart
authors.initials: B
authors.lastname: Jonckx
authors.forename: Masahiro
authors.initials: M
authors.lastname: Murakami
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Lanahan
authors.forename: Christof
authors.initials: C
authors.lastname: Michielsen
authors.forename: David
authors.initials: D
authors.lastname: Sibrac
authors.forename: Frédérique
authors.initials: F
authors.lastname: Dol-Gleizes
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Serena
authors.initials: S
authors.lastname: Zacchigna
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Herault
authors.forename: Christian
authors.initials: C
authors.lastname: Fischer
authors.forename: Patrice
authors.initials: P
authors.lastname: Rigon
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz de Almodovar
authors.forename: Filip
authors.initials: F
authors.lastname: Claes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Blanc
authors.forename: Koen
authors.initials: K
authors.lastname: Poesen
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Segura
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gueguen
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Bordes
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Roselyne
authors.initials: R
authors.lastname: Broussy
authors.forename: Marlies
authors.initials: M
authors.lastname: van de Wouwer
authors.forename: Corinne
authors.initials: C
authors.lastname: Michaux
authors.forename: Toru
authors.initials: T
authors.lastname: Shimada
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jean
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.forename: Patrick
authors.initials: P
authors.lastname: Motte
authors.forename: Eran
authors.initials: E
authors.lastname: Rom
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Rakic
authors.forename: Susumu
authors.initials: S
authors.lastname: Katsuma
authors.forename: Paul
authors.initials: P
authors.lastname: Schaeffer
authors.forename: Avner
authors.initials: A
authors.lastname: Yayon
authors.forename: Ann
authors.initials: A
authors.lastname: Van Schepdael
authors.forename: Harald
authors.initials: H
authors.lastname: Schwalbe
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.forename: Jef
authors.initials: J
authors.lastname: Rozensky
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001862:Bone Resorption / Q000188:drug therapy; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D054852:Small Molecule Libraries; D005346:Fibroblast Growth Factors; D020794:Receptor Protein-Tyrosine Kinases