2. Academic Validation
  3. Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists

Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists

  • Eur J Med Chem. 2022 Nov 5:241:114627. doi: 10.1016/j.ejmech.2022.114627.
Ancheng Shen 1,  Xiyuan Li 2,  Yan Zhang 3,  Jing Ma 4,  Ruoxuan Xiao 4,  Xiyuan Wang 3,  Zilan Song 4,  Zhiguo Liu 5,  Meiyu Geng 6,  Ao Zhang 1,  Zuoquan Xie 7,  Chunyong Ding 8
Affiliations

Affiliations

  • 1 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 5 School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zqxie@simm.ac.cn.
  • 8 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: chunding@sjtu.edu.cn.
PMID: 35963129 DOI: 10.1016/j.ejmech.2022.114627
Abstract

Pharmacological activation of stimulator of interferon genes (STING) by agonists has emerged as a new modality of Cancer Immunotherapy. However, current available STING agonists remain in early developmental stage or failed in clinic trials due to limited efficacy in humans. In this report, we performed a structure-activity relationship study based on the benzothiophene oxobutanoic acid scaffold of MSA-2, a well-documented STING agonist by Merck, leading to a series of N-substituted acyloxyamino derivatives with potent STING activating effect. Among them, compounds 57 and 60 displayed the most potent activity specifically targeting both h- and m-STING. Particularly, 57 displayed more potent and rapid activation of the STING signaling pathway than ADU-S100 in THP1-Dual cells. In vivo anti-tumor efficacy of 57 by intratumoral or oral administration was also demonstrated in several mouse tumor models. Intriguingly, treatment with 57 eradicated all the CT26 tumor without further recurrence in all treated mice, which could also reject the same tumor re-inoculation, indicating an induction of immune memory by 57. Taken together, acyloxyamino derivative 57 represents a new chemotype of STING agonist with well-demonstrated in vivo anti-tumor activity, which is deserved for further investigation.

Keywords

Immuno-oncology; Innate immunity; STING Agonists; Structural modification.

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