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

干扰素基因刺激剂 化学 兴奋剂 体内 药理学 苯并噻吩 干扰素 结构-活动关系 免疫系统 免疫疗法 癌症研究 受体 先天免疫系统 体外 生物化学 免疫学 医学 生物技术 有机化学 生物 工程类 噻吩 航空航天工程
作者
Ancheng Shen,Xiyuan Li,Yan Zhang,Jing Ma,Ruoxuan Xiao,Xiyuan Wang,Zilan Song,Zhiguo Liu,Meiyu Geng,Ao Zhang,Zuoquan Xie,Chunyong Ding
出处
期刊:European journal of medicinal chemistry [Elsevier BV]
卷期号:241: 114627-114627 被引量:10
标识
DOI:10.1016/j.ejmech.2022.114627
摘要

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.
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