Targeting Tumor Angiogenesis With TSP-1-based Compounds: Rational Design of Antiangiogenic Mimetics of Endogenous Inhibitors

Oncotarget. 2010 Nov;1(7):662-73. doi: 10.18632/oncotarget.101108.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis*
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Biomimetics / methods
  • Biomimetics / trends
  • Drug Design*
  • Humans
  • Models, Biological
  • Models, Molecular
  • Molecular Targeted Therapy / methods*
  • Neoplasms / blood supply
  • Neoplasms / drug therapy*
  • Neovascularization, Pathologic / drug therapy*
  • Rationalization
  • Thrombospondin 1 / chemistry*
  • Thrombospondin 1 / physiology

Substances

  • Angiogenesis Inhibitors
  • Thrombospondin 1