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

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.

Jie Zhang | Harald Schwalbe | Francesco Luigi Gervasio | Arthur Christopoulos | Isabelle Blanc | Marc Bianciotto | Diether Lambrechts | Christian Fischer | Michael Simons | Geert Carmeliet | Mieke Dewerchin | Peter Carmeliet | Avner Yayon | Toru Shimada | Serena Zacchigna | David Sibrac | Corinne Michaux | Corentin Herbert | Françoise Bono | Susumu Katsuma | J. Rakic | P. Carmeliet | H. Schwalbe | A. Van Schepdael | D. Lambrechts | T. Shimada | A. Christopoulos | F. Gervasio | F. De Smet | S. Katsuma | G. Carmeliet | J. Herbert | S. Blacher | M. Dewerchin | M. Mazzone | S. Zacchigna | M. Simons | A. Yayon | A. Noel | F. Bono | A. Lanahan | M. Bianciotto | C. Herbert | I. Blanc | M. Tjwa | M. Georgiadou | K. Poesen | K. De Bock | Silvia Blacher | P. Fons | A. Ny | Marc Tjwa | Frederik De Smet | Inmaculada Segura | Katrien De Bock | Bart Jonckx | Maria Georgiadou | Pierre Fons | Chantal Alcouffe | Annelii Ny | Masahiro Murakami | Anthony A Lanahan | Christof Michielsen | Frédérique Dol-Gleizes | Massimiliano Mazzone | Jean-Pascal Herault | Patrice Rigon | Carmen Ruiz de Almodovar | Filip Claes | Koen Poesen | Geneviève Gueguen | Marie-Françoise Bordes | Roselyne Broussy | Marlies van de Wouwer | Isabelle Jean | Agnès Noel | Patrick Motte | Eran Rom | Jean-Marie Rakic | Paul Schaeffer | Ann Van Schepdael | Jef Rozensky | Jean-Marc Herbert | Filip Claes | I. Segura | C. Fischer | P. Schaeffer | B. Jonckx | M. Murakami | Carmen Ruiz de Almodóvar | M. van de Wouwer | M. Bordes | Jie Zhang | C. Alcouffe | C. Michaux | P. Motte | F. Dol-Gleizes | E. Rom | G. Gueguen | J. Herault | Isabelle Jean | D. Sibrac | Christof Michielsen | P. Rigon | Roselyne Broussy | Jef Rozensky | Katrien De Bock

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