Cover Picture: Identification and Structure of Small-Molecule Stabilizers of 14–3–3 Protein–Protein Interactions (Angew. Chem. Int. Ed. 24/2010)

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Angewandte Chemie International Edition (Impact Factor: 11.34). 06/2010; 49(24). DOI: 10.1002/anie.201002255
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    ABSTRACT: Full text free access until 31st January 2014. Classical target-based drug discovery, where large chemical libraries are screened using inhibitory assays for a single target, has struggled to find ligands that inhibit protein-protein interactions (PPI). Nevertheless, in the past decade there have been successes that have demonstrated that PPI can be useful drug targets, and the field is now evolving fast. This review focuses on the new approaches and concepts that are being developed to tackle these challenging targets: the use of fragment based methods to explore the chemical space, stapled peptides to regulate intracellular PPI, alternatives to competitive inhibition and the use of antibodies to enable small molecule discovery for these targets.
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    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.
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