SSR128129E (SSR) allosterically inhibits FGFR by binding the FGFR extracellular domain.

  • Major finding: SSR128129E (SSR) allosterically inhibits FGFR by binding the FGFR extracellular domain.

  • Clinical relevance: SSR blocks tumor growth and angiogenesis alone and in combination with VEGFR inhibition.

  • Impact: Allosteric inhibitors that act extracellularly can be developed to inhibit oncogenic RTK signaling.

Fibroblast growth factor receptors (FGFR) are receptor tyrosine kinases (RTK) that play key roles in cell proliferation, inflammation, and angiogenesis. Existing strategies to inhibit FGFR and other RTKs include competitive inhibition of ligand binding or receptor dimerization and inhibition of kinase activity. Along these lines, Bono and colleagues conducted a high-throughput chemical screen to identify inhibitors of FGF2 binding to FGFR1. Unexpectedly, one compound was identified that inhibited FGF2-induced endothelial cell proliferation and migration with nanomolar potency despite only inhibiting FGF2 binding at micromolar levels. This compound, SSR128129E (SSR), specifically inhibited all FGFR superfamily members but did not affect FGF ligand binding in cell-based assays, inhibit FGFR kinase activity, or cross the plasma membrane, suggesting an extracellular and allosteric mechanism of action distinct from known RTK inhibitors. Herbert and colleagues further confirmed that SSR is an allosteric FGFR inhibitor and characterized its activity using nuclear magnetic resonance, crystallography, infrared spectroscopy, in silico modeling and simulations, and mutagenesis of predicted SSR-interacting FGFR residues, which collectively indicated that SSR binds to a site in the FGFR extracellular domain that is distinct from the ligand-binding site and induces conformational changes in the extracellular domain that reduce FGFR internalization and signaling. Notably, SSR was orally bioavailable and well tolerated in mice and significantly inhibited FGFR-driven processes such as growth, metastasis, inflammatory cell infiltration, and angiogenesis in multiple tumor models. Moreover, SSR potentiated the effects of a VEGF receptor (VEGFR) inhibitor on tumor growth and increased VEGFR inhibitor sensitivity in a refractory cell line, consistent with a compensatory role of FGFRs following VEGFR inhibition. The identification and subsequent characterization of SSR as an orally active multi-FGFR inhibitor with an extracellular, allosteric mechanism of action thus has implications for both FGFR-targeted and antiangiogenic therapy and provides a framework for an additional strategy for RTK inhibition.

Bono F, De Smet F, Herbert C, De Bock K, Georgiadou M, Fons P, et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell 2013;23:477–88.

Herbert C, Schieborr U, Saxena K, Juraszek J, De Smet F, Alcouffe C, et al. Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell 2013;23:489–501.