Discovery of INCB191358: A Potent and Selective DGKα/ζ Dual Inhibitor.

Diacylglycerol kinases α and ζ (DGKα/ζ) negatively regulate T-cell receptor signaling, limiting T-cell effector function and antitumor immunity. Dual DGKα/ζ inhibition therefore represents a promising strategy to enhance T-cell activity and improve responses to checkpoint blockade. Herein, we describe the discovery of a 2-purinone-based series of dual DGKα/ζ inhibitors. A high-throughput screening campaign identified selective DGKα hits, and incorporation of a 2-purinone core enabled dual DGKα/ζ activity. Substitution of the 2-purinone scaffold markedly enhanced potency, leading to compound . Although exhibited potent activity and balanced ADME properties, in vivo evaluation revealed a flat pharmacokinetic profile attributable to its benzhydryl substituent. Structure-activity relationship studies demonstrated that incorporation of a 4-phenoxypiperidine improved pharmacokinetic properties and culminated in the discovery of INCB191358 (), a potent, selective, and orally bioavailable dual DGKα/ζ inhibitor. In vivo, achieved transient, yet highly efficacious target coverage, inducing antigen-dependent T-cell activation in a mouse pharmacodynamic model and enhancing antitumor efficacy in a syngeneic tumor model when combined with PD-1 blockade.