Development of pH-Resilient Boronic Acid ENPP1 Inhibitors for STING-Mediated Cancer Immunotherapy

Abstract Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) hydrolyzes cGAMP within the tumor microenvironment (TME), suppressing stimulator of interferon genes (STING)-mediated antitumor immunity. Inspired by the phosphate-based inhibitor STF-1084, we developed a novel class of non-nucleotide ENPP1 inhibitors featuring a boronic acid zinc-binding group (ZBG), which led to the identification of the potent and pH-resilient compound 36. In vitro evaluations confirmed that compound 36 enhances cGAMP-mediated STING activation, driving the upregulation of key immune effectors and chemokines. Furthermore, in a syngeneic CT26 tumor model, monotherapy with compound 36 (20 mg/kg, IP) achieved a tumor growth inhibition (TGI) of 57.4%. Notably, combination therapy with a single dose of oxaliplatin (OX) exhibited a synergistic antitumor effect (TGI = 80.7%) without observable toxicity. Collectively, this study identifies compound 36 as a promising lead ENPP1 inhibitor and further highlights boronic acid as an effective ZBG for the development of ENPP1-targeted cancer immunotherapies.