[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bono, Francoise
De Smet, Frederik
Herbert, Corentin
De Bock, Katrien
Georgiadou, Maria
Fons, Pierre
Tjwa, Marc
Alcouffe, Chantal
Ny, Annelii
Bianciotto, Marc
Jonckx, Bart
Murakami, Masahiro
Lanahan, Anthony A.
Michielsen, Christof
Sibrac, David
Dol-Gleizes, Frederique
Mazzone, Massimiliano
Zacchigna, Serena
Herault, Jean-Pascal
Fischer, Christian
Rigon, Patrice
Ruiz de Almodovar, Carmen
Claes, Filip
Blanc, Isabelle
Poesen, Koen
Zhang, Jie
Segura, Inmaculada
Gueguen, Genevieve
Bordes, Marie-Francoise
Lambrechts, Diether
Broussy, Roselyne
van de Wouwer, Marlies
Michaux, Corinne
Shimada, Toru
Jean, Isabelle
Blacher, Silvia ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Motte, Patrick ; Université de Liège - ULiège > Département des sciences de la vie > Génomique fonctionnelle et imagerie moléculaire végétale
Rom, Eran
Rakic, Jean-Marie ; Université de Liège - ULiège > Département des sciences cliniques > Ophtalmologie
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