Discovery of a photoactivatable dimerized STING agonist based on the benzo[b]selenophene scaffold

Stimulator of interferon genes (STING) agonism presents a powerful weapon for cancer immunotherapy. This study reports a novel dimerized STING agonist diBSP01, which exhibited promising STING binding and activation properties in vitro, based on the benzo[b]selenophene scaffold. Meanwhile, shielding the pharmacophores of diBSP01 with photoremovable protecting groups (PPGs) resulted in the generation of the first photoactivatable STING agonist, caged-diBSP01, that exerted no biological potency in the absence of light stimulation while regaining its STING agonistic activity after 400 nm irradiation. Optically controlled in vivo anticancer activity was also proven with caged-diBSP01 in a zebrafish xenograft model. Our study provides insights into developing novel STING agonists for cancer treatment and a solution for precise STING activation to avoid the on-target systemic inflammatory response responsible for normal cell damage caused by systemic STING agonism.

Automated summary

This study introduces a novel dimerized STING agonist, diBSP01, which shows promising binding and activation properties for STING in vitro with the benzo[b]selenophene scaffold. Additionally, the study presents the development of the first photoactivatable STING agonist, caged-diBSP01, which demonstrates no biological potency without light stimulation but regains its STING agonistic activity after 400 nm irradiation. The optically controlled in vivo anticancer activity of caged-diBSP01 is also validated in a zebrafish xenograft model.