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 importantroles in cancer immunotherapy by activating innate immuneresponses. We designed and synthesized STING modulators andcharacterized compounds4aand4cthat share a crucialamidobenzimidazole moiety.In vitroSTING binding and cell-based activity assays demonstrated the potency and efficacy of thecompounds that function as direct STING agonists by stimulatingSTING downstream signaling and promoting type I interferonimmune responses.In vitrometabolic studies and the pharmaco-kinetic properties of the compounds led us to investigate theiranticancer activity in anin vivosyngeneic model.Intravenousinjection of compounds4aand4csignificantly decreased tumorvolume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived cancer inhibition was observed in4c-treated mouse models. The present results suggest the therapeutic potential of the compounds for cancer immunotherapy via STING-mediated immune activation