Design, Synthesis, and Biological Assessment of Novel Aminobenzidazole Agonists Targeting the Stimulator of Interferon Genes Receptor Signaling Pathway for Oncology Immunotherapy

The activation of the STING-mediated signaling pathway leads to the secretion of type I interferon (IFN) and the activation of tumor-specific T cells. STING, a pattern recognition receptor located on the endoplasmic reticulum membrane of immune cells, binds with endogenous cyclic dinucleotides. STING undergoes phosphorylation, triggering the STING-TBK1-IRF3 pathway and NF-κB pathway, resulting in the release of IFN-β and other pro-inflammatory cytokines, ultimately enhancing the activation of tumor-specific T cells. This mechanism serves to complement the limitations of immune checkpoint inhibitors and enhances the efficiency of the immune response. This study selected benzimidazole compounds GSK and SR-717, which exhibit promising potential as patented medicines, as our lead compounds. Aiming to address the challenges associated with the short half-life of benzimidazole compounds and the limited molecular activity of SR-717, we designed and synthesized a series of STING agonists (compounds 6~29). The compound 17 showed excellent agonistic activity on hSTING protein in vitro. The cytotoxicity tests of all the synthesized compounds were performed in vitro. Performed in vivo pharmacokinetic studies on the most promising compounds and conducted molecular docking analyses.