Discovery of 14-3-3 Protein- Protein Interaction Inhibitors that Sensitize Multidrug- Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693
Article (Published version)
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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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.
Related to: https://ibiss-r.rcub.bg.ac.rs/handle/123456789/3886.
Keywords:antitumor agents; cancer; doxorubicin; inhibitors; multidrug resistance; protein-protein interactions
Source:Chemmedchem, 2014, 9, 5, SI, 973-983
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