Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor

Abstract

Stimulator of interferon genes (STING) is an endoplasmic reticulum-membrane protein that plays important roles in cancer immunotherapy by activating innate immune responses. We designed and synthesized STING modulators and characterized compounds <b>4a</b> and <b>4c</b> that share a crucial amidobenzimidazole moiety. <i>In vitro</i> STING binding and cell-based activity assays demonstrated the potency and efficacy of the compounds that function as direct STING agonists by stimulating STING downstream signaling and promoting type I interferon immune responses. <i>In vitro</i> metabolic studies and the pharmacokinetic properties of the compounds led us to investigate their anticancer activity in an <i>in vivo</i> syngeneic model<i>.</i> Intravenous injection of compounds <b>4a</b> and <b>4c</b> significantly decreased tumor volume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived cancer inhibition was observed in <b>4c</b>-treated mouse models. The present results suggest the therapeutic potential of the compounds for cancer immunotherapy via STING-mediated immune activation<b>.</b>