Discovery of Fluoroalkenes as Dual Inhibitors of Diacylglycerol Kinases Alpha and Zeta (DGKα/ζ)

Diacylglycerol kinases alpha and zeta (DGKα/ζ) are negative regulators of T cell receptor signaling that suppress immune system activation. As such, dual inhibition of DGKα and ζ represents a promising strategy to enhance antitumor immunity, making these kinases attractive targets for cancer immunotherapy. Herein, we report the discovery of a series of fluoroalkenes as potent dual inhibitors of DGKα and ζ. A high-throughput screening campaign identified amide 1 with micromolar activity against DGKζ. While SAR studies revealed amides with potent dual DGKα/ζ activity, replacing the amide with a fluoroalkene bioisostere led to a significant improvement in cellular activity. Systematic SAR studies led to the discovery of lead compound 17, a potent dual DGKα/ζ inhibitor with balanced in vitro ADME properties and favorable pharmacokinetic profiles. The in vivo functional activity of compound 17 was demonstrated in an OT-1 pharmacodynamic murine model, showing robust and dose-dependent immune activation in the presence of antigen presentation.