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


Song Z(1)(2)(3), Wang X(1)(4), Zhang Y(1)(4), Gu W(1)(2), Shen A(1)(2), Ding C(2), Li H(1)(3), Xiao R(2), Geng M(1)(4), Xie Z(1)(4), Zhang A(1)(2)(3)(4)(5).
Author information:
(1)State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica
(SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
(2)Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
(3)College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023 China.
(4)University of Chinese Academy of Sciences, Beijing 100049, China.
(5)State Key Laboratory of Esophageal Cancer Prevention and Treatment, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China.


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.