Discovery of a non-nucleotide STING agonist with antitumor activity

Activation of the STING pathway has demonstrated significant potential as a cancer immunotherapeutic strategy. Given the persistent challenges in cancer therapy, the development of STING agonists with improved efficacy and multifunctionality is of paramount importance. Through phenotypic high-throughput screening (HTS), we identified 17 compounds capable of activating the STING-IRF3 pathway and inducing interferon-β (IFN-β) expression. Further characterization revealed that compound 09-B11 binds STING with measurable affinity. Structural analyses demonstrated that two molecules of 09-B11 bind each STING dimer in an “open” conformation. Moreover, 09-B11 induced the mRNA expression of downstream cytokines IFN-β and CXCL10 in a concentration-dependent manner, and activated the STING signaling pathway. In addition, the compound effectively suppressed tumor growth in an MC38 murine syngeneic model. Collectively, our findings indicate that 09-B11, a non-nucleotide STING agonist, exhibits moderate antitumor activity and can serve as a candidate for further research.