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: 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.
    ChemMedChem 05/2014; 9(5). DOI:10.1002/cmdc.201400044 · 3.05 Impact Factor
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    ABSTRACT: One of the proteins that is found in a diverse range of eukaryotic protein-protein interactions is the adaptor protein 14-3-3. As 14-3-3 is a hub protein with very diverse interactions, it is a good model to study various protein-protein interactions. A wide range of classes of molecules, peptides, small molecules or natural products, has been used to modify the protein interactions, providing both stabilization or inhibition of the interactions of 14-3-3 with its binding partners. The first protein crystal structures were solved in 1995 and gave molecular insights for further research. The plant analog of 14-3-3 binds to a plant plasma membrane H(+)-ATPase and this protein complex is stabilized by the fungal phytotoxin fusicoccin A. The knowledge gained from the process in plants was transferred to and applied in human models to find stabilizers or inhibitors of 14-3-3 interaction in human cellular pathways.
    Future medicinal chemistry 05/2014; 6(8):903-21. DOI:10.4155/fmc.14.47 · 4.00 Impact Factor
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    ABSTRACT: Protein–protein interactions (PPIs) are implicated in every disease and mastering the ability to influence PPIs with small molecules would considerably enlarge the druggable genome. Whereas inhibition of PPIs has repeatedly been shown to work successfully, targeted stabilization of PPIs is underrepresented in the literature. This is all the more surprising because natural products like FK506, rapamycin, brefeldin, forskolin and fusicoccin confer their physiological activity by stabilizing specific PPIs. However, recently a number of very interesting synthetic molecules have been reported from drug discovery projects that indeed achieve their desired activities by stabilizing either homo- or hetero-oligomeric complexes of their target proteins.
    Drug Discovery Today 11/2014; DOI:10.1016/j.drudis.2014.08.005 · 5.96 Impact Factor

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