Design, Synthesis and Biological Evaluation of Novel, Potent, Selective and Orally Available DGKα Inhibitors for the Treatment of Tumors.

The diacylglycerol kinase alpha (DGKα) is an important player in signal transduction, phosphorylating the membrane lipid diacylglycerol to phosphatidic acid. Emerging data indicate that DGKα mediates T cell dysfunction during anti-PD-1 therapy, having a marked impact on the development of resistance to PD-1 blockade. Here, we report the discovery of compound 10 as a novel, potent, selective, and orally available DGKα inhibitor with a promising ADME profile. More importantly, compound 10 significantly enhanced the in vivo antitumor activities by combination with anti-PD-1 or anti-CTLA-4 in different mouse models, and obvious synergistic effects were observed.