Synthetic sulfoglycolipids targeting the serine-threonine protein kinase Akt.
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.
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Barbara
B
Costa
Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Saldini 50, 20133 Milan, Italy.
Milind
M
Dangate
Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Saldini 50, 20133 Milan, Italy.
Maria
M
Vetro
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Giulia
G
Donvito
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Luca
L
Gabrielli
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Loredana
L
Amigoni
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.
Giuliana
G
Cassinelli
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.
Cinzia
C
Lanzi
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Michela
M
Ceriani
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Luca
L
De Gioia
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Giulia
G
Filippi
Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy.
Laura
L
Cipolla
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.
Nadia
N
Zaffaroni
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: paola.perego@istitutotumori.mi.it.
Paola
P
Perego
Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Saldini 50, 20133 Milan, Italy.
Diego
D
Colombo
D004797:Enzyme-Linked Immunosorbent Assay; D006017:Glycolipids / Q000378:metabolism*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship
D006017:Glycolipids; C011117:sulfoglycolipids; D051057:Proto-Oncogene Proteins c-akt
Akt; Cancer; Inhibitors; Phosphatidyl inositol analogues; Sulfoquinovose