Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy
Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy
复制标题
DOI：
10.1016/j.bmcl.2019.126640
复制
发表时间：
2019-10-15
影响因子：
2.7
通讯作者：
Di Francesco, M. Emilia
中科院分区：
文献类型：
--
作者：
Ager, Casey R.;Zhang, Huaping;Di Francesco, M. Emilia
外源性和内源性细胞质DNA激活干扰素基因刺激因子（STING）通路导致干扰素β (ifn - β)的产生，并且是产生针对肿瘤抗原的细胞毒性t细胞启动所必需的。在临床环境中，药物刺激STING通路有可能通过增强抗肿瘤免疫反应与免疫治疗抗体协同作用。我们报道了两种高效的环二核苷酸STING激动剂IACS-8803和IACS-8779的发现，与一种临床基准化合物相比，它们在体外显示出强大的STING途径激活，并且在B16小鼠黑色素瘤模型中具有优越的全身抗肿瘤反应。
Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-beta) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In the clinical setting, pharmacological stimulation of the STING pathway has the potential to synergize with immunotherapy antibodies by boosting anti-tumor immune responses. We report the discovery of two highly potent cyclic dinucleotide STING agonists, IACS-8803 and IACS-8779, which show robust activation of the STING pathway in vitro and a superior systemic anti-tumor response in the B16 murine model of melanoma when compared to one of the clinical benchmark compounds.