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.

Structure-based virtual screening allows the identification of efficient modulators of E-cadherin-mediated cell-cell adhesion / Dalle Vedove, A.; Falchi, F.; Donini, S.; Dobric, A.; Germain, S.; Martino, G. P. D.; Prosdocimi, T.; Vettraino, C.; Torretta, A.; Cavalli, A.; Rigot, V.; Andre, F.; Parisini, E.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 20:14(2019), p. 3404. [10.3390/ijms20143404]

Structure-based virtual screening allows the identification of efficient modulators of E-cadherin-mediated cell-cell adhesion

Dalle Vedove A.;Cavalli A.;
2019-01-01

Abstract

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.
2019
14
Dalle Vedove, A.; Falchi, F.; Donini, S.; Dobric, A.; Germain, S.; Martino, G. P. D.; Prosdocimi, T.; Vettraino, C.; Torretta, A.; Cavalli, A.; Rigot, V.; Andre, F.; Parisini, E.
Structure-based virtual screening allows the identification of efficient modulators of E-cadherin-mediated cell-cell adhesion / Dalle Vedove, A.; Falchi, F.; Donini, S.; Dobric, A.; Germain, S.; Martino, G. P. D.; Prosdocimi, T.; Vettraino, C.; Torretta, A.; Cavalli, A.; Rigot, V.; Andre, F.; Parisini, E.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 20:14(2019), p. 3404. [10.3390/ijms20143404]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/277665
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 15
  • ???jsp.display-item.citation.isi??? 16
social impact