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Title: Discovery of 14-3-3 Protein-Protein Interaction Inhibitors that Sensitize Multidrug-Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693
Authors: Mori, Mattia 
Vignaroli, Giulia
Cau, Ylenia
Dinić, J
Hill, R
Rossi, M
Colecchia, D
Pešić, M
Link, W
Chiariello, M
Ottmann, C
Botta, Maurizio 
Issue Date: 2014
Project: None 
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
ISSN: 1860-7187
DOI: 10.1002/cmdc.201400044
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