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

• Published in: Journal of medicinal chemistry 2021-02, Vol.64 (3), p.1649-1669
• Main Authors: Song, Zilan, Wang, Xiyuan, Zhang, Yan, Gu, Wangting, Shen, Ancheng, Ding, Chunyong, Li, Han, Xiao, Ruoxuan, Geng, Meiyu, Xie, Zuoquan, Zhang, Ao
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Benzimidazoles - chemical synthesis; Benzimidazoles - pharmacokinetics; Benzimidazoles - pharmacology; Humans; Membrane Proteins - agonists; Mice; Mice, Inbred BALB C; Models, Molecular; Solubility; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01900

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.