Discovery of 14-3-3 protein-protein interaction inhibitors that sensitize multidrug-resistant cancer cells to doxorubicin and the Akt inhibitor GSK690693.

Mattia Mori, Giulia Vignaroli, Ylenia Cau, Jelena Dinić, Richard Hill, Matteo Rossi, David Colecchia, Milica Pešić, Wolfgang Link, Mario Chiariello, Christian Ottmann, Maurizio Botta

ChemMedChem 2014 May

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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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Mattia Mori, Giulia Vignaroli, Ylenia Cau, Jelena Dinić, Richard Hill, Matteo Rossi, David Colecchia, Milica Pešić, Wolfgang Link, Mario Chiariello, Christian Ottmann, Maurizio Botta. Discovery of 14-3-3 protein-protein interaction inhibitors that sensitize multidrug-resistant cancer cells to doxorubicin and the Akt inhibitor GSK690693. ChemMedChem. 2014 May;9(5):973-83