Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors

Chiara Foglieni, Katiuscia Pagano, Marco Lessi, Antonella Bugatti, Elisabetta Moroni, Denise Pinessi, Andrea Resovi, Domenico Ribatti, Sabrina Bertini, Laura Ragona, Fabio Bellina, Marco Rusnati, Giorgio Colombo, Giulia Taraboletti

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Abstract

The FGFs/FGFRs system is a recognized actionable target for therapeutic approaches aimed at inhibiting tumor growth, angiogenesis, metastasis, and resistance to therapy. We previously identified a non-peptidic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Here we identified new small molecule inhibitors of FGF2 based on the initial lead. A similarity-based screening of small molecule libraries, followed by docking calculations and experimental studies, allowed selecting 7 bi-naphthalenic compounds that bound FGF2 inhibiting its binding to both heparan sulfate proteoglycans and FGFR-1. The compounds inhibit FGF2 activity in in vitro and ex vivo models of angiogenesis, with improved potency over SM27. Comparative analysis of the selected hits, complemented by NMR and biochemical analysis of 4 newly synthesized functionalized phenylamino-substituted naphthalenes, allowed identifying the minimal stereochemical requirements to improve the design of naphthalene sulfonates as FGF2 inhibitors.

Original languageEnglish
Article number23432
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Mar 22 2016

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Foglieni, C., Pagano, K., Lessi, M., Bugatti, A., Moroni, E., Pinessi, D., Resovi, A., Ribatti, D., Bertini, S., Ragona, L., Bellina, F., Rusnati, M., Colombo, G., & Taraboletti, G. (2016). Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors. Scientific Reports, 6, [23432]. https://doi.org/10.1038/srep23432