Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties

Francesco Bono, Frederik De Smet, Corentin Herbert, Katrien De Bock, Maria Georgiadou, Pierre Fons, Marc Tjwa, Chantal Alcouffe, Annelii Ny, Marc Bianciotto, Bart Jonckx, Masahiro Murakami, Anthony A Lanahan, Christof Michielsen, David Sibrac, Frederique Dol-Gleizes, Massimiliano Mazzone, Serena Zacchigna, Jean-Pascal Herault, Christian FischerPatrice Rigon, Carmen Ruiz de Almodovar, Filip Claes, Isabelle Blanc, Koen Poesen, Zie Zhang, Immaculada Segura, Genevieve Gueguen, Marie-Francoise Bordes, Diether Lambrechts, Roselyne Broussy, Marlies van de Wouwer, Corinne Michaux, Toru Shimada, Isabelle Jean, Silvia Blacher, Agnes Noel, Patrick Motte, Eran Rom, Jean-Marie Rakic, Susumu Katsuma, Paul Schaeffer, Avner Yayon, Ann Van Schepdael, Harald Schwalbe, Francesco L Gervasio, Geert Carmeliet, Jef Rozensky, Mieke Dewerchin, Michael Simons, Arthur Christopoulos, Jean-Marc Herbert, Peter Carmeliet

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117 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)477 - 488
Number of pages12
JournalCancer Cell
Issue number4
Publication statusPublished - 2013

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