Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors
| Autor: | Daniela Capello, Maria Talmon, Andrea Graziani, L. Fresu, Alberto Massarotti, Alessandra Galetto, Gianluca Baldanzi, Suresh Velnati, Gian Cesare Tron, Alessandra Bertoni, Annamaria Antona, Valentina Mercalli |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular structure–activity relationship Indoles Cell Survival T-Lymphocytes Diacylglycerol kinase RM1-950 Computational biology 01 natural sciences Monocytes Piperazines Dose-Response Relationship Structure-Activity Relationship Models Cell Movement enzyme assays kinase inhibitors molecular modelling Dose-Response Relationship Drug HEK293 Cells Humans Lipoprotein Lipase Lymphocytes MCF-7 Cells Molecular Structure Protein Kinase Inhibitors Drug Discovery Structure–activity relationship Pharmacology Virtual screening 010405 organic chemistry Chemistry Molecular General Medicine 0104 chemical sciences 010404 medicinal & biomolecular chemistry Identification (biology) Therapeutics. Pharmacology Drug Research Paper |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 96-108 (2020) |
| DOI: | 10.6084/m9.figshare.10259531.v1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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