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.