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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 proliferatio...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248139/ https://www.ncbi.nlm.nih.gov/pubmed/21317461 |
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author | Taraboletti, Giulia Rusnati, Marco Ragona, Laura Colombo, Giorgio |
author_facet | Taraboletti, Giulia Rusnati, Marco Ragona, Laura Colombo, Giorgio |
author_sort | Taraboletti, Giulia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3248139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-32481392012-01-18 Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors Taraboletti, Giulia Rusnati, Marco Ragona, Laura Colombo, Giorgio Oncotarget Research Perspectives 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. Impact Journals LLC 2010-11-25 /pmc/articles/PMC3248139/ /pubmed/21317461 Text en Copyright: © 2010 Taraboletti et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
spellingShingle | Research Perspectives Taraboletti, Giulia Rusnati, Marco Ragona, Laura Colombo, Giorgio Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors |
title | Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors |
title_full | Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors |
title_fullStr | Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors |
title_full_unstemmed | Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors |
title_short | Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors |
title_sort | targeting tumor angiogenesis with tsp-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors |
topic | Research Perspectives |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248139/ https://www.ncbi.nlm.nih.gov/pubmed/21317461 |
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