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

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.