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

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

  • J Med Chem. 2021 Feb 11;64(3):1649-1669. doi: 10.1021/acs.jmedchem.0c01900.
Zilan Song 1 2 3,  Xiyuan Wang 1 4,  Yan Zhang 1 4,  Wangting Gu 1 2,  Ancheng Shen 1 2,  Chunyong Ding 2,  Han Li 1 3,  Ruoxuan Xiao 2,  Meiyu Geng 1 4,  Zuoquan Xie 1 4,  Ao Zhang 1 2 3 4 5
Affiliations

Affiliations

  • 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.
PMID: 33470814 DOI: 10.1021/acs.jmedchem.0c01900
Abstract

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.

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