Structure–Activity Relationship Study of Amidobenzimidazole Analogues Leading to Potent and Systemically Administrable Stimulator of Interferon Gene (STING) Agonists

Activation
of the stimulator of interferon gene (STING) has emerged
as an exciting immuno-oncology therapeutic strategy; however, the
first-generation STING agonists, cyclic dinucleotide (CDN) analogues,
have suffered from many disadvantages and failed in clinical trials.
Therefore, non-CDN small-molecule STING agonists are urgently needed.
In view of the unique structure of the high potency of dimeric amidobenzimidazole
STING agonist 5, a structural elaboration was conducted
by modifying several structural hotspots of this scaffold. Triazole 40 was identified as a new potent STING activator, possessing
EC50 values of 0.24 and 39.51 μM for h- and m-STING,
respectively. This compound has a slightly better pharmacokinetic
profile and is >20-fold more aqueously soluble than 5. It activated the STING signaling dramatically by directly binding
and stabilizing all h-STING isoforms and m-STING. In vivo, intermittent
administration of 40 was found to have significant antitumor
efficacy with good tolerance in two mouse tumor models.