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

作者：Zilan Song, Xiyuan Wang, Yan Zhang, Wangting Gu, Ancheng Shen, Chunyong Ding, Li Han, Ruoxuan Xiao, Meiyu Geng, Zuoquan Xie, Ao Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.0c01900 · 被引用次数：45 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Inflammasome and immune disorders

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 EC 50 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.