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.

中文翻译：

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在Amb639752上进行结构活性关系研究：用于鉴定DGKα抑制剂的常见药效结构。

我们最近通过虚拟筛选发现了Amb639752的一系列类似物，Amb639752是一种新型的二酰基甘油激酶（DGK）抑制剂。这些化合物被评估为α，θ和ζ同工型的DGK抑制剂，以及5-羟色胺受体的拮抗剂。从这些试验中发现了两种新型化合物，即11和20，其IC50分别为1.6和1.8 µM，是迄今为止发现的最有效的DGKα抑制剂。两种化合物均显示出在X连锁淋巴组织增生性疾病的细胞模型中恢复凋亡的能力，以及减少癌细胞迁移的能力，表明它们在预防转移中的潜在效用。最后，依靠实验生物学数据，分子建模研究使我们能够为DGK抑制剂建立三点药效团模型。