Discovery of BMS-986408, a First-In-Class Dual DGK⍺ and DGK Inhibitor That Unleashes PD-1 Checkpoint and CAR-T Cell Immunotherapies

DGKα and DGKζ are lipid kinases that negatively regulate T cell signaling through diacylglycerol (DAG) metabolism, making them attractive targets for next-generation immunotherapy. Here, we disclose the discovery and pre-clinical characterization of the first 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 DAG-substrate competitive inhibition, subcellular translocation to 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 uniquely amplifying the priming and expansion of tumor-reactive T cells in the tumor-draining lymph nodes. Importantly, simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. DGKα and DGKζ were broadly expressed in NSCLC tumor-infiltrated T cells and combination therapy invigorated a robust cytokine response in NSCLC patient-derived organotypic tumors supporting the clinical evaluation of this combination in NSCLC patients. BMS-986408 also markedly improved CD19-targeted CAR-T cell therapy efficacy by overcoming hypo-functionality, insufficient expansion, and lack of co-stimulatory ligands. BMS-986408 represents the first critical step towards evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in cancer patients.