1689P OATD-02 validates the benefits of pharmacological inhibition of arginase 1 and 2 in cancer

Arginases play important roles in the metabolic pathways determining fitness of both immune and tumour cells. ARG1 expressed by myeloid cells microenvironment (TME) contributes to suppression effector functions T NK a local L-arginine depletion, while ARG2 constitutes cell-autonomous regulator cytotoxic regulatory lymphocytes. is highly various cancers its significant role cancer has recently emerged as levels correlate with malignant phenotype poor prognosis. These observations unveil arginases especially well-validated promising therapeutic targets. OATD-02 only dual inhibitor, which due unique pharmacokinetic properties ability target intracellular ARG2, can address benefit arginase inhibition cancer. The inhibitory activity was determined vitro using recombinant human well cellular systems primary hepatocytes macrophages. In vivo, antitumor evaluated murine syngeneic models colorectal renal carcinomas (CT26 Renca, respectively), leukaemia xenograft model (K562). potent inhibitor necessary for targeting ARG2. Compared extracellular activity, we have shown improved efficacy CT26 immunomodulatory effect reflected Treg RCC Renca model. Importantly, had superior when combined other immunotherapeutics. Finally, showed ARG2-dependent anticancerous on CML small-molecule optimal drug-like properties. Thanks excellent against long drug-target residence time, high volume distribution slow clearance, significantly differs from inhibitors. represents very drug candidate treatment tumours pharmacological tool, effectively benefits inhibition. will enter clinical trials 2022.