BMS-986408 (BMS-408) is a potent, selective, DAG substrate competitive dual DGKα and DGKζ lipid kinase inhibitor with IC50 of 3 nM and 20 nM respectively, >100-fold selectivity for DGKα over DGKβ and DGKγ.
BMS-986408 inhibits DGKζ and DGKι with similar potency, shows no significant activity for Type II (DGKδ, DGKη, DGKκ), Type III (DGKε, or Type V (DGKθ) family members. BMS-986408 induces the translocation of both YFP-DGKα (EC50=0.026 µM) and YFP-DGKζ (EC50=0.008 µM) from cytoplasm to plasma membrane.
BMS-986408 also induces the degradation of both DGKα and DGKζ, which is ubiquitin and proteosome dependent.
BMS-986408 shows potent amplification of phospho-ERK in both CD4+ (EC50=0.008 µM) and CD8+ (EC50=0.012 µM) T cells and IL-2 production (Donor 1 EC50 0.019 µM; Donor 2 EC50 0.034 µM).
BMS-986408 amplified the antigen-specific activation of naïve mouse OT-1 CD8+ T cells by autologous BMDCs cross-presenting OVA, as measured by proliferation (EC50=0.015 µM) and IL-2 production (EC50=0.022 µM).
BMS-986408 also amplified the antigen specific killing of NY-ESO-1 antigen presenting SAOS-2 cells by human T cells transduced with NY-ESO-1 TCR (EC50=0.001 µM).
BMS-986408 binds to the accessory subdomain of the DGKα and DGKζ catalytic domain.
BMS-986408 broadly amplify T cell–mediated tumor immunity and invigorate both PD-1 immune checkpoint and CAR T-cell therapy.