Discovery of BMS-986408, a First-In-Class Dual DGKα and DGKζ Inhibitor that Unleashes PD-1 Checkpoint and CAR T-cell Immunotherapies.

ABSTRACT: Diacylglycerol kinase α (DGKα) and DGKζ are lipid kinases that negatively regulate T-cell signaling through diacylglycerol metabolism, making them attractive targets for next-generation immunotherapy. In this study, we report the discovery and preclinical characterization of the clinical-stage DGKα and DGKζ lipid kinase inhibitor, BMS-986408. BMS-986408 binds to the accessory subdomain of the catalytic domain and inhibits DGKα/ζ through a mechanism of action that includes competitive inhibition for the diacylglycerol substrate, subcellular translocation to the plasma membrane, and proteosome-dependent degradation. DGKα/ζ inhibition markedly improved the therapeutic benefit of PD-1 therapy by unleashing T-cell responses in the tumor while also amplifying the priming and expansion of tumor-r

SUBMITTER: Wichroski M 

PROVIDER: S-EPMC12402804 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature