Molecular basis of the antiangiogenic action of rosmarinic acid, a natural compound targeting Fibroblast Growth Factor-2/FGFR interactions

Fibroblast growth factor (FGF2)/Fibroblast growth factor Receptor (FGFR) signalling plays a major role both in physiology and in several pathologies, including cancer development, metastasis formation and resistance to therapy. The development of small molecules, acting extracellularly to target FGF2/FGFR interactions, has the advantage of limiting adverse effects associated to the current intracellular FGFR inhibitors. Here we discuss the ability of the natural compound rosmarinic acid (RA) to induce FGF2/FGFR complex dissociation. The molecular level description of FGF2/FGFR/RA system, by NMR and docking, clearly demonstrates that RA binds to FGFR-D2 domain and directly competes with FGF2 for the same binding site. Both direct and allosteric perturbations concur to destabilize the complex. The proposed molecular mechanism is validated by cellular studies showing that RA inhibits FGF2-induced endothelial cells proliferation and FGFR activation. Our results can serve as the basis for the development of new extracellular inhibitors of the FGF/FGFR pathways.