Definition

An orally bioavailable boronic acid derivative and inhibitor of arginase 1 (ARG1) and 2 (ARG2), with potential immunomodulating and antineoplastic activities. Upon oral administration, ARG1/ARG2 inhibitor OATD-02 selectively inhibits ARG1 and ARG2, thereby preventing the breakdown of arginine by arginase and restoring arginine levels. This allows arginine to stimulate the synthesis of nitric oxide (NO) and the secretion of pro-inflammatory cytokines and chemokines, which induces the proliferation and activation of T cells. Therefore, this agent may prevent the immunosuppressive effects of tumor-infiltrating myeloid cells, inhibit the immunomodulatory effect induced by regulatory T cells (Tregs), and promote lymphocyte-mediated immune responses against tumor cells. In addition, inhibition of ARG-mediated signaling may also kill tumor cells and decrease tumor cell growth by modulating tumor metabolism. Arginase, a manganese-dependent enzyme that hydrolyzes the amino acid arginine to form ornithine and urea, is produced by neutrophils, macrophages and myeloid-derived suppressor cells (MDSC). It plays a key role in inflammation-associated immunosuppression, tumor immunity, tumor cell growth and in metabolic pathways. Overexpressed in various types of tumors, its overexpression correlates with poor prognosis due to diminished arginine levels.