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Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion

Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for...

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Autores principales: Dalle Vedove, Andrea, Falchi, Federico, Donini, Stefano, Dobric, Aurelie, Germain, Sebastien, Di Martino, Giovanni Paolo, Prosdocimi, Tommaso, Vettraino, Chiara, Torretta, Archimede, Cavalli, Andrea, Rigot, Veronique, André, Frederic, Parisini, Emilio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678102/
https://www.ncbi.nlm.nih.gov/pubmed/31373305
http://dx.doi.org/10.3390/ijms20143404
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author Dalle Vedove, Andrea
Falchi, Federico
Donini, Stefano
Dobric, Aurelie
Germain, Sebastien
Di Martino, Giovanni Paolo
Prosdocimi, Tommaso
Vettraino, Chiara
Torretta, Archimede
Cavalli, Andrea
Rigot, Veronique
André, Frederic
Parisini, Emilio
author_facet Dalle Vedove, Andrea
Falchi, Federico
Donini, Stefano
Dobric, Aurelie
Germain, Sebastien
Di Martino, Giovanni Paolo
Prosdocimi, Tommaso
Vettraino, Chiara
Torretta, Archimede
Cavalli, Andrea
Rigot, Veronique
André, Frederic
Parisini, Emilio
author_sort Dalle Vedove, Andrea
collection PubMed
description Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell–cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell–cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell–cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers.
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spelling pubmed-66781022019-08-19 Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion Dalle Vedove, Andrea Falchi, Federico Donini, Stefano Dobric, Aurelie Germain, Sebastien Di Martino, Giovanni Paolo Prosdocimi, Tommaso Vettraino, Chiara Torretta, Archimede Cavalli, Andrea Rigot, Veronique André, Frederic Parisini, Emilio Int J Mol Sci Article Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell–cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell–cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell–cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers. MDPI 2019-07-11 /pmc/articles/PMC6678102/ /pubmed/31373305 http://dx.doi.org/10.3390/ijms20143404 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dalle Vedove, Andrea
Falchi, Federico
Donini, Stefano
Dobric, Aurelie
Germain, Sebastien
Di Martino, Giovanni Paolo
Prosdocimi, Tommaso
Vettraino, Chiara
Torretta, Archimede
Cavalli, Andrea
Rigot, Veronique
André, Frederic
Parisini, Emilio
Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion
title Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion
title_full Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion
title_fullStr Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion
title_full_unstemmed Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion
title_short Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion
title_sort structure-based virtual screening allows the identification of efficient modulators of e-cadherin-mediated cell–cell adhesion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678102/
https://www.ncbi.nlm.nih.gov/pubmed/31373305
http://dx.doi.org/10.3390/ijms20143404
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