title: Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors.
abstract: 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 TSP-1/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.
authors.affiliation: Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
authors.affiliation: Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.affiliation: Istituto per lo Studio delle Macromolecole, Consiglio Nazionale delle Ricerche, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ragona
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D032701:Biomimetics / Q000379:methods / Q000639:trends; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011908:Rationalization; D019700:Thrombospondin 1 / Q000737:chemistry* / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D019700:Thrombospondin 1