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

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. Pièce de résistance! Multidrug resistance (MDR) is the main obstacle toward effective anticancer therapy. Herein we report the discovery of two small-molecule 14-3-3 protein-protein interaction inhibitors that promote the translocation of c-Abl and FOXO pro-apoptotic factors into the nucleus and sensitize MDR cancer cells to doxorubicin and the pan-Akt inhibitor GSK690693. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.