Abstract
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.
Highlights
Diacylglycerol kinases (DGKs) are a large family of enzymes that share a common catalytic activity: the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA)
The biological relevance of DGKa is best demonstrated in patients with X-linked lymphoproliferative disease (XLP-1), who experience life-threatening, uncontrolled accumulation of CD8þ T cells in response to the Epstein–Barr virus (EBV) infection[6]
Each inhibitor was tested in duplicate at least once, and DGKa activity was expressed as percentage of residual DGKa activity compared to DMSO control in the same assay
Summary
Diacylglycerol kinases (DGKs) are a large family of enzymes that share a common catalytic activity: the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). The compound was totally devoid of inhibitory activity on the enzyme, showing the importance of the basic nitrogen atom for the anti-serotoninergic activity, and for the interaction with the kinase With this in mind, we recently used an in-silico approach based on chemical homology with the two commercially available DGKa inhibitors R59022 and R59949 using the programmes ROCS28 and EON29. We identified a compound, Amb639752 (Figure 2), featuring a lower IC50 for DGKa than ritanserin (IC501⁄417 mM), a better selectivity for the a-isoform and devoid of anti-serotoninergic activity. Preparation of tert-butyl 4-(2-(2,6-dimethyl-1H-indol-3-yl)-2oxoethyl)piperazine-1-carboxylate (6) Under nitrogen, 200 mg of 5 (0.90 mmol, 1 eq) was dissolved in toluene dry, N-Boc-piperazine (0.17 g, 0.90 mmol, 1 eq), K2CO3 (0.32 g, 2.25 mmol, 2.5 eq), and KI
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