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.

Costa, B., Dangate, M., Vetro, M., Donvito, G., Gabrielli, L., Amigoni, L., et al. (2016). Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt. BIOORGANIC & MEDICINAL CHEMISTRY, 24(16), 3396-3405 [10.1016/j.bmc.2016.05.031].

Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt

COSTA, BARBARA SIMONA
Primo
;
DANGATE, MILIND
Secondo
;
DONVITO, GIULIA;GABRIELLI, LUCA;AMIGONI, LOREDANA;CERIANI, MICHELA;DE GIOIA, LUCA;FILIPPI, GIULIA;CIPOLLA, LAURA FRANCESCA;
2016

Abstract

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.
Articolo in rivista - Articolo scientifico
Akt; Cancer; Inhibitors; Phosphatidyl inositol analogues; Sulfoquinovose;
Akt; Cancer; Inhibitors; Phosphatidyl inositol analogues; Sulfoquinovose; Biochemistry; Clinical Biochemistry; Molecular Biology; Molecular Medicine; Organic Chemistry; Drug Discovery3003 Pharmaceutical Science; 3003
English
15-ago-2016
2016
24
16
3396
3405
none
Costa, B., Dangate, M., Vetro, M., Donvito, G., Gabrielli, L., Amigoni, L., et al. (2016). Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt. BIOORGANIC & MEDICINAL CHEMISTRY, 24(16), 3396-3405 [10.1016/j.bmc.2016.05.031].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/132569
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