Design, Synthesis, and Biological Evaluation of Amidobenzimidazole Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists

Stimulator of interferon genes (STING) is an endoplasmic
reticulum-localized
adaptor protein (STING receptor) that has been shown to be activated
by binding to natural cyclic dinucleotide (CDN) ligands and plays
a vital role in innate immune sensing of exogenous or endogenous DNA,
which then induces type I interferons and other cytokines. In this
paper, we described a series of amidobenzimidazole STING agonists
with high potency for the STING receptor and presented the relevant
structure–activity relationships (SARs). The relative potencies
of compounds 16g, 24b, and 24e were measured by a STING competition binding assay. A more thorough
study of the effect on the STING signaling pathway demonstrated that
three compounds, 16g, 24b, and 24e, significantly increased the protein levels and mRNA levels of IFN-β,
CXCL10, and IL-6, and 24b as a representative compound
effectively triggered the phosphorylation of STING, TBK1, and IRF3
in both human peripheral blood mononuclear cells (hPBMCs) and WT THP-1
cells. In addition, compound 24b demonstrated impressive
antitumor efficacy in mice with established syngeneic colon tumors
by intravenous administration. Furthermore, the pharmacokinetic profile
of compound 24b was fully evaluated.