Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors
A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel...
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Taylor & Francis Group
2020-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | http://dx.doi.org/10.1080/14756366.2019.1684911 |
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doaj-3339702823c34737b631d4896dd549e82021-07-15T13:10:31ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742020-01-013519610810.1080/14756366.2019.16849111684911Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitorsSuresh Velnati0Alberto Massarotti1Annamaria Antona2Maria Talmon3Luigia Grazia Fresu4Alessandra Silvia Galetto5Daniela Capello6Alessandra Bertoni7Valentina Mercalli8Andrea Graziani9Gian Cesare Tron10Gianluca Baldanzi11Department of Translational Medicine, University of Piemonte OrientaleDepartment of Pharmaceutical Sciences, University of Piemonte OrientaleDepartment of Translational Medicine, University of Piemonte OrientaleDepartment of Health Sciences, School of Medicine, University of Piemonte OrientaleDepartment of Health Sciences, School of Medicine, University of Piemonte OrientaleDepartment of Translational Medicine, University of Piemonte OrientaleDepartment of Translational Medicine, University of Piemonte OrientaleDepartment of Translational Medicine, University of Piemonte OrientaleDepartment of Pharmaceutical Sciences, University of Piemonte OrientaleUniversità Vita-Salute San RaffaeleDepartment of Pharmaceutical Sciences, University of Piemonte OrientaleDepartment of Translational Medicine, University of Piemonte OrientaleA series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.http://dx.doi.org/10.1080/14756366.2019.1684911diacylglycerol kinasekinase inhibitorsstructure–activity relationshipenzyme assaysmolecular modelling |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Suresh Velnati Alberto Massarotti Annamaria Antona Maria Talmon Luigia Grazia Fresu Alessandra Silvia Galetto Daniela Capello Alessandra Bertoni Valentina Mercalli Andrea Graziani Gian Cesare Tron Gianluca Baldanzi |
| spellingShingle |
Suresh Velnati Alberto Massarotti Annamaria Antona Maria Talmon Luigia Grazia Fresu Alessandra Silvia Galetto Daniela Capello Alessandra Bertoni Valentina Mercalli Andrea Graziani Gian Cesare Tron Gianluca Baldanzi Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry diacylglycerol kinase kinase inhibitors structure–activity relationship enzyme assays molecular modelling |
| author_facet |
Suresh Velnati Alberto Massarotti Annamaria Antona Maria Talmon Luigia Grazia Fresu Alessandra Silvia Galetto Daniela Capello Alessandra Bertoni Valentina Mercalli Andrea Graziani Gian Cesare Tron Gianluca Baldanzi |
| author_sort |
Suresh Velnati |
| title |
Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors |
| title_short |
Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors |
| title_full |
Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors |
| title_fullStr |
Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors |
| title_full_unstemmed |
Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors |
| title_sort |
structure activity relationship studies on amb639752: toward the identification of a common pharmacophoric structure for dgkα inhibitors |
| publisher |
Taylor & Francis Group |
| series |
Journal of Enzyme Inhibition and Medicinal Chemistry |
| issn |
1475-6366 1475-6374 |
| publishDate |
2020-01-01 |
| description |
A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors. |
| topic |
diacylglycerol kinase kinase inhibitors structure–activity relationship enzyme assays molecular modelling |
| url |
http://dx.doi.org/10.1080/14756366.2019.1684911 |
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