14-3-3 is a family of highly conserved adapter proteins that is attracting much interest among medicinal chemists. Small-molecule inhibitors of 14-3-3 protein-protein interactions (PPIs) are in high demand, both as tools to increase our understanding of 14-3-3 actions in human diseases and as leads to develop innovative therapeutic agents. Herein we present the discovery of novel 14-3-3 PPI inhibitors through a multidisciplinary strategy combining molecular modeling, organic synthesis, image-based high-content analysis of reporter cells, and in vitro assays using cancer cells. Notably, the two most active compounds promoted the translocation of c-Abl and FOXO pro-apoptotic factors into the nucleus and sensitized multidrug-resistant cancer cells to apoptotic inducers such as doxorubicin and the pan-Akt inhibitor GSK690693, thus becoming valuable lead candidates for further optimization. Our results emphasize the possible role of 14-3-3 PPI inhibitors in anticancer combination therapies

Mori, M., Vignaroli, G., Cau, Y., Dinić, J., Hill, R., Rossi, M., et al. (2014). Discovery of 14-3-3 Protein-Protein Interaction Inhibitors that Sensitize Multidrug-Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693. CHEMMEDCHEM, 9(5), 973-983 [10.1002/cmdc.201400044].

Discovery of 14-3-3 Protein-Protein Interaction Inhibitors that Sensitize Multidrug-Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693

MORI, MATTIA;VIGNAROLI, GIULIA;CAU, YLENIA;BOTTA, MAURIZIO
2014-01-01

Abstract

14-3-3 is a family of highly conserved adapter proteins that is attracting much interest among medicinal chemists. Small-molecule inhibitors of 14-3-3 protein-protein interactions (PPIs) are in high demand, both as tools to increase our understanding of 14-3-3 actions in human diseases and as leads to develop innovative therapeutic agents. Herein we present the discovery of novel 14-3-3 PPI inhibitors through a multidisciplinary strategy combining molecular modeling, organic synthesis, image-based high-content analysis of reporter cells, and in vitro assays using cancer cells. Notably, the two most active compounds promoted the translocation of c-Abl and FOXO pro-apoptotic factors into the nucleus and sensitized multidrug-resistant cancer cells to apoptotic inducers such as doxorubicin and the pan-Akt inhibitor GSK690693, thus becoming valuable lead candidates for further optimization. Our results emphasize the possible role of 14-3-3 PPI inhibitors in anticancer combination therapies
Mori, M., Vignaroli, G., Cau, Y., Dinić, J., Hill, R., Rossi, M., et al. (2014). Discovery of 14-3-3 Protein-Protein Interaction Inhibitors that Sensitize Multidrug-Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693. CHEMMEDCHEM, 9(5), 973-983 [10.1002/cmdc.201400044].
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/11365/46176
 Attenzione

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