Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors

Inhibitors of angiogenesis are an important addition to conventional
chemotherapy. Among different ``druggable'' angiogenic factors,
fibroblast growth factor-2 (FGF-2) is an attractive target for novel
therapies because of its intricated involvement in tumor
neovascularization, tumor cell proliferation and migration, and the
acquisition of resistance to antiangiogenic therapies. FGF-2
bioavailability and activity is affected by several natural ligands,
including the endogenous inhibitor of angiogenesis thrombospondin-1
(TSP-1). We hypothesized that the FGF-2-binding sequence of TSP-1 might
serve as a template for the development of non-peptide inhibitors of
angiogenesis. Computational biology and nuclear magnetic resonance
spectroscopy approaches, major investigative tools in the
characterizations of protein-protein interaction (PPI), were used to map
the residues at the TSP1/FGF-2 interface. The translation of this
three-dimensional information into a pharmacophore model allowed
screening a small molecule databases, identifying three FGF-2-binding,
antiangiogenic small molecules, mimetic of TSP-1. Pharmacophore-based
approaches are thus feasible tools to exploit naturally occurring PPI,
by generating a set of lead compounds mimetic of endogenous proteins, as
a starting point for the development of novel therapeutic agents.