Discovery of Novel, Potent, Selective, and Orally Available DGKα Inhibitors for the Treatment of Tumors.

DGKα, also named diacylglycerol kinase alpha, plays an important role in signal transduction, phosphorylating the membrane lipid diacylglycerol (DAG), to phosphatidic acid (PA). Increasing evidence indicates that DGKα-mediated T-cell dysfunction plays a significant role in the development of resistance of the PD-1 blockade. In this article, we report the discovery of compound 16 as a novel, potent, orally available DGKα inhibitor with excellent kinase selectivity, a favorable ADME profile, and robust in vivo antitumor activity in combination with anti-PD-1 therapy.