DGK alpha/zeta inhibitor BMS-986408

An orally bioavailable inhibitor of both the alpha-isoenzyme of diacylglycerol kinase (DGK-alpha; DGKa) and the zeta-isoenzyme DGK-zeta (DGKz), with potential immune checkpoint inhibitory and antineoplastic activities. Upon oral administration, DGK alpha/zeta inhibitor BMS-986408 targets, binds to and blocks both DGKa and DGKz expressed on T cells, thereby preventing the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). This induces DAG-mediated T-cell receptor (TCR)-mediated T-cell signaling, induces T-cell proliferation, restores T-cell function, enhances cytokine production, and activates a cytotoxic T-cell-mediated anti-tumor immune response. In addition, inhibition of DGKa and DGKz, overexpressed on certain tumor cells, may induce apoptosis and inhibit proliferation. DGKa and DGKz are involved in the negative regulation of second messenger signaling through lipid phosphorylation. Highly expressed in T lymphocytes, DGKa and DGKz regulate TCR signaling, promote T-cell anergy, and play a key role in the downregulating of T-cell responses in tumors. DGKa and DGKz, also highly expressed in various cancers, promote cancer cell survival through its anti-apoptosis and pro-proliferation activities.