Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties.

[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

More authors (43 more)

Language :

English

Title :

Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties.

Publication date :

2013

Journal title :

Cancer Cell

ISSN :

1535-6108

eISSN :

1878-3686

Publisher :

Elsevier Science

Volume :

Issue :

Pages :

477-88

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 29 May 2013

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