CB-1158 dihydrochloride is an orally bioavailable, potent (IC50 = 98 nM), and selective (minimal off-target activity at 50000 nM) inhibitor of human arginase I, an immune-mediated anti-tumor agent. L-arginine is a critical metabolite for T-cell receptor signaling and subsequent T-cell proliferation, and depletion of arginine arrests T-cell growth. In the tumor microenvironment, infiltrating myeloid-derived suppressor cells (MDSCs), macrophages, and neutrophils produce arginase, which depletes local arginine concentrations and dampens T cell-mediated immune surveillance. Pharmacological inhibition of arginase is expected to restore arginine levels and allow T-cells to proliferate, thereby leading to an immune-mediated anti-tumor response. In culture, human granulocytes release arginase and deplete media arginine to levels that inhibit T-cell proliferation. In a co-culture system of human granulocytes and T-cells, CB-1158 dihydrochloride potently blocks granulocyte-derived arginase activity, maintains extracellular arginine levels, and restores proliferation of T-cells. CB-1158 dihydrochloride has single agent efficacy in mouse tumor models and synergistically enhances the antitumor efficacy of checkpoint inhibitors.

KEYWORDS: CB-1158 dihydrochloride | Supplier | Arginase inhibitor | Numidargista dihydrochloride | INCB-01158 dihydrochloride | CB 1158 | CB1158 | INCB01158 | INCB 01158 |  CT-CB1158 | CAS [N.A.] | [2095732-06-0] | Arginine | Arginase | Inhibitor | Enzymes