Definition

An orally bioavailable selective small molecule inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), with potential immunomodulating and antineoplastic activities. Upon oral administration, ENPP1 inhibitor SR-8541A selectivelly targets and binds to ENPP1, thereby inhibiting the activity of ENPP1. This inhibits ENPP1-mediated 2′-3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and adenosine triphosphate (ATP) hydrolysis and stabilizes extracellular endogenous cGAMP and ATP. This leads to the extracellular accumulation of cGAMP and ATP, and inhibits the production and accumulation of immunosuppressive adenosine in the tumor microenvironment (TME). This allows for the activation of stimulator of interferon genes (STING), and the induction of anticancer immune responses. ENPP1, overexpressed in a number of tumor types, mediates nucleotide recycling by breaking down ATP to AMP, which is then converted to adenosine. It suppresses anti-tumor immune responses and increases metastasis.