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.