350 (PB130) - An orally bioavailable ENPP1-selective inhibitor demonstrates superior immune preservation effects over STING agonists and confers antitumor efficacy in combination with other therapies in syngeneic tumor models

Abstract

Background: The cGAS-cGAMP-STING pathway plays a crucial role in both tumor and immune cells to promote anti-tumor immunity. Preclinically, synthetic STING agonists have shown promise, but have not demonstrated robust clinical efficacy potentially due to detrimental effects on immune cells which may compromise anti-tumor efficacy. ENPP1, an ectonucleotide pyrophosphatase/phosphodiesterase that catalyzes the hydrolysis of the endogenous STING agonist 2′,3′-cGAMP, is a negative regulator of STING activation and its inhibition represents an alternative way to stimulate the STING pathway that would potentially spare the immune damaging effects associated with hyperactivation of STING.