Human specific STING agonists for the treatment of cancer

项目总结 细胞先天免疫感受器，如刺激物(干扰素基因的刺激物)，已经进化到 检测细胞的微生物感染(1-3)。斯汀控制着强大的胞浆DNA刺激的先天免疫 途径，并被由分泌的环二核苷酸(CDN)激活，如cDGMP和cDAMP 感染后的细胞内细菌。或者，刺痛可以被环化的GMP-AMP(CGAMP)激活 细胞内cGAMP合成酶cGAS(MB21D1)与胞浆dsDNA结合后产生 物种，可包括从细胞核泄漏的微生物DNA或自身DNA(4)。与CDN的关联 使刺痛能够激活I型干扰素(干扰素)和促炎细胞因子的产生， 促进适应性免疫(3)。除了对防止微生物感染至关重要外，刺痛 信号已被证明是促进强大的抗肿瘤免疫的关键。对 免疫系统激发抗肿瘤细胞毒性T细胞反应被证明是治疗 有效治疗多种癌症。例如，基于合成CDN的刺激剂已经被 显示出可能通过刺激APC发挥强大的抗肿瘤特性，目前正在进行I期评估 治疗癌症的试验。然而，这种CDN是高度不稳定的，在以下情况下不会发挥有效的活性 有系统地给予。这将它们的使用/评估限制在肿瘤内和口服给药上。在这里，我们 描述新一代激活STING信号的新一代小型STING激动剂，它们似乎优于 现有的CDN，用于评估抗肿瘤治疗策略。这些化合物是由以下物质产生的 总部设在迈阿密的STINGINN LLC，与佛罗里达州迈阿密大学医学院合作。

PROJECT SUMMARY Cellular innate immune sensors, such as STING (STIMULATOR OF INTERFERON GENES), have evolved to detect microbial infection of the cell (1-3). STING controls the potent cytosolic DNA-stimulated innate immune pathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted by intracellular bacteria following infection. Alternatively, STING can be activated by cyclic GMP-AMP (cGAMP) generated by a cellular cGAMP synthase cGAS (MB21D1) after association with aberrant cytosolic dsDNA species, which can include microbial DNA or self-DNA leaked from the nucleus (4). Association with CDNs enables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines, which facilitate adaptive immunity (3). Aside from being critical for the protection against microbial infection, STING signaling has been shown to be essential for facilitating robust anti-tumor immunity. Regulation of the immune system to stimulate anti-tumor cytotoxic T cell responses is proving to be a powerful approach for the effective treatment of a variety of cancers. For example, STING agonists, based on synthetic CDNs, have been shown to exert potent anti-tumor properties likely by stimulating APCs and are now being evaluated in Phase I trials for the treatment of cancer. However, such CDNs are highly labile and do not exert potent activity when given systemically. This has limited their use/evaluation to intratumoral and oral administration. Here, we describe a new generation of novel small STING agonists that activate STING signaling, that appear superior to existing CDN’s, for evaluation in anti-tumor therapeutic strategies. The compounds have been generated by STINGINN LLC, based in Miami, in collaboration with the University of Miami School of Medicine, FL.