Feng Xi, Pan Lixia, Qian Zhiyu, Liu Dongyu, Guan Xin, Feng Li, Song Bin, Xu Xi, Tan Ninghua, Ma Yi, Li Zhiyu, Wang Zhe, Bian Jinlei
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, Department of TCMs Pharmaceuticals, China Pharmaceutical University, Nanjing 211100, P. R. China.
State Key Laboratory of Non-Food Biomass and Enzyme Technology, Guangxi Academy of Sciences, Nanning 530007, P. R. China.
J Med Chem. 2022 Nov 24;65(22):15048-15065. doi: 10.1021/acs.jmedchem.2c00634. Epub 2022 Sep 7.
Activation of the stimulator of interferon genes (STING) pathway to achieve antitumor response is an attractive approach for cancer immunotherapy. In this study, we report the identification of () as a potent, orally available STING agonist. strongly activates STING signaling in human and mouse cells and binds STING as a homodimer. A 2.4 Å cocrystal structure revealed that could induce the "closed" conformation of STING. studies revealed that is well tolerated, has an excellent pharmacokinetic profile as an oral drug, and induces tumor regression and durable antitumor immunity. The promising bioactivities of make it valuable for further development as an antitumor agent.
激活干扰素基因刺激因子（STING）通路以实现抗肿瘤反应是癌症免疫治疗的一种有吸引力的方法。在本研究中，我们报告鉴定出（）作为一种有效的、口服可用的STING激动剂。（）在人和小鼠细胞中强烈激活STING信号，并作为同二聚体结合STING。一个2.4埃的共晶体结构表明（）可诱导STING的“封闭”构象。（）的研究表明，（）耐受性良好，作为口服药物具有优异的药代动力学特征，并可诱导肿瘤消退和持久的抗肿瘤免疫。（）有前景的生物活性使其作为一种抗肿瘤药物具有进一步开发的价值。
