Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor
Min Jae Jeon, Hyelim Lee, Jeehee Lee, Soo Yeon Baek, Dong-Hee Lee, Seongman Jo, Joo‐Youn Lee, Miso Kang, Hee Ra Jung, Soo Bong Han, Nam‐Jung Kim, Sanghee Lee, Hyejin Kim
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 4a and 4c that share a crucial amidobenzimidazole moiety. In vitro 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. In vitro metabolic studies and the pharmacokinetic properties of the compounds led us to investigate their anticancer activity in an in vivo syngeneic model. Intravenous injection of compounds 4a and 4c significantly decreased tumor volume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived cancer inhibition was observed in 4c-treated mouse models. The present results suggest the therapeutic potential of the compounds for cancer immunotherapy via STING-mediated immune activation.