Definition

An orally bioavailable inhibitor of the alpha-isoenzyme of diacylglycerol kinase (DGK-alpha; DGKa), with potential immune checkpoint inhibitory and antineoplastic activities. Upon oral administration, DGKa inhibitor GS-9911 targets, binds to and blocks DGKa 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. This induces apoptosis and suppresses proliferation of susceptible tumor cells. DGKa is involved in the negative regulation of second messenger signaling through lipid phosphorylation. DGKa is highly expressed in various cancers and promotes cancer cell survival through its anti-apoptosis and pro-proliferation activities. Also highly expressed in T lymphocytes, DGKa regulates TCR signaling, promotes T-cell anergy, and plays a key role in the downregulating of T-cell responses in tumors.