Design, synthesis, and STING-agonistic activity of benzo[ b ]thiophene-2-carboxamide derivatives

STING is an important immune-associated protein that localizes in the endoplasmic reticulum membrane. Upon being activated by its agonists, STING triggers the IRF and NF-κB pathways, which generates type I interferons and proinflammatory cytokines, and ultimately primes the innate immune responses to achieve valid antitumor efficacy. We designed and synthesized a series of benzo[ b ]thiophene-2-carboxamide derivatives. Through STING-agonistic activity evaluation, compounds 12d and 12e exhibited marginal human STING-activating activities. Western blot analysis demonstrated that both 12d and 12e treatment increased the phosphorylation of the downstream signaling molecules (TBK1 and IRF3) of STING. The proposed binding mode of 12d / 12e and STING protein displayed that two canonical hydrogen bonds, a π-π stacking interaction, as well as a π- cation interaction formed between the agonist and the CDN-binding domain of STING protein. Graphical abstract