Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt
| Autor: | Giulia Filippi, Nadia Zaffaroni, Barbara Costa, Diego Colombo, M. Vetro, Luca De Gioia, Laura Cipolla, Loredana Amigoni, Giuliana Cassinelli, Paola Perego, Milind Dangate, Cinzia Lanzi, Giulia Donvito, Michela Ceriani, Luca Gabrielli |
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| Přispěvatelé: | Costa, B, Dangate, M, Vetro, M, Donvito, G, Gabrielli, L, Amigoni, L, Cassinelli, G, Lanzi, C, Ceriani, M, DE GIOIA, L, Filippi, G, Cipolla, L, Zaffaroni, N, Perego, P, Colombo, D |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Inhibitor Proto-Oncogene Proteins c-akt Clinical Biochemistry Pharmaceutical Science AKT1 Enzyme-Linked Immunosorbent Assay Serine threonine protein kinase Biochemistry 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Akt Cancer Inhibitors Phosphatidyl inositol analogues Sulfoquinovose Molecular Medicine Molecular Biology 3003 Drug Discovery3003 Pharmaceutical Science Organic Chemistry Drug Discovery CHIM/06 - CHIMICA ORGANICA Humans Protein kinase A Protein kinase B BIO/14 - FARMACOLOGIA PI3K/AKT/mTOR pathway Phosphatidyl inositol analogue Chemistry Akt/PKB signaling pathway Spectrum Analysis BIO/11 - BIOLOGIA MOLECOLARE Cell biology Pleckstrin homology domain 030104 developmental biology 030220 oncology & carcinogenesis Glycolipids |
| Popis: | The serine-threonine protein kinase Akt, also known as protein kinase B, is a key component of the phosphoinositide 3-kinase (PI3K)-Akt-mTOR axis. Deregulated activation of this pathway is frequent in human tumors and Akt-dependent signaling appears to be critical in cell survival. PI3K activation generates 3-phosphorylated phosphatidylinositols that bind Akt pleckstrin homology (PH) domain. The blockage of Akt PH domain/phosphoinositides interaction represents a promising approach to interfere with the oncogenic potential of over-activated Akt. In the present study, phosphatidyl inositol mimics based on a β-glucoside scaffold have been synthesized as Akt inhibitors. The compounds possessed one or two lipophilic moieties of different length at the anomeric position of glucose, and an acidic or basic group at C-6. Docking studies, ELISA Akt inhibition assays, and cellular assays on different cell models highlighted 1-O-octadecanoyl-2-O-β-d-sulfoquinovopyranosyl-sn-glycerol as the best Akt inhibitor among the synthesized compounds, which could be considered as a lead for further optimization in the design of Akt inhibitors. |
| Databáze: | OpenAIRE |
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