Description
R-59-949 is an inhibitor of diacylglycerol kinase α (DGK-α) with an IC
50 value of 300 nM in isolated platelet plasma membranes using exogenous diacylglycerol as a substrate. DGK-α inhibition with R-59-949 increases diacylglycerol-dependent PKC activity, serotonin secretion, and aggregation of thrombin-stimulated platelets. R-59-949 inhibits DGK-α activity induced by platelet-derived growth factor (PDGF) in intact vascular smooth muscle cells (VSMCs). It inhibits high K
+- and glucose-induced insulin secretion in MIN6 pancreatic β-cells in a dose-dependent manner.
In vivo, administration of R-59-949 prevents retinal neovascularization in a mouse model of oxygen-induced retinopathy.
Uses
Diacylglycerol Kinase Inhibitor II has been used to determine tumor-induced inhibition with genetically modified cytotoxic T cells expressing chimeric antigen receptors (CAR). It has also been used to induce pAkt and PKR-like extracellular signal-regulated kinase (pErk) signals in T-cell acute lymphoblastic leukemia (T-ALL) cells.
Definition
ChEBI: 3-[2-[4-[bis(4-fluorophenyl)methylidene]-1-piperidinyl]ethyl]-2-sulfanylidene-1H-quinazolin-4-one is a diarylmethane.
Biochem/physiol Actions
Diacylglycerol kinase inhibitor. Inhibits formation of [38P]1-Oleoyl-2-acetylglyceryl-3-phosphoric acid (OAPA) in red blood cell membranes: IC50 = 3.3 μM.
References
[1] D DE CHAFFOY DE COURCELLES. The role of endogenously formed diacylglycerol in the propagation and termination of platelet activation. A biochemical and functional analysis using the novel diacylglycerol kinase inhibitor, R 59 949.[J]. The Journal of Biological Chemistry, 1989, 264 6: 3274-3285.
[2] X. DU. Fatty acids inhibit growth-factor-induced diacylglycerol kinase alpha activation in vascular smooth-muscle cells.[J]. The Ukrainian Biochemical Journal, 2001, 1 1: 275-282. DOI:
10.1042/bj3570275[3] YUKIKO KUROHANE KANEKO. Depression of type I diacylglycerol kinases in pancreatic β-cells from male mice results in impaired insulin secretion.[J]. Endocrinology, 2013, 154 11: 4089-4098. DOI:
10.1210/en.2013-1356[4] LU YANG. Diacylglycerol Kinase (DGK) Inhibitor II (R59949) Could Suppress Retinal Neovascularization and Protect Retinal Astrocytes in an Oxygen-Induced Retinopathy Model[J]. Journal of Molecular Neuroscience, 2014, 56 1: 78-88. DOI:
10.1007/s12031-014-0469-2
