Novartis NIBR ATI, 4056 Basel, Switzerland.
Cells. 2022 Mar 29;11(7):1159. doi: 10.3390/cells11071159.
The cGAS STING pathway has received much attention in recent years, and it has been recognized as an important component of the innate immune response. Since the discovery of STING and that of cGAS, many observations based on preclinical models suggest that the faulty regulation of this pathway is involved in many type I IFN autoinflammatory disorders. Evidence has been accumulating that cGAS/STING might play an important role in pathologies beyond classical immune diseases, as in, for example, cardiac failure. Human genetic mutations that result in the activation of STING or that affect the activity of cGAS have been demonstrated as the drivers of rare interferonopathies affecting young children and young adults. Nevertheless, no data is available in the clinics demonstrating the therapeutic benefit in modulating the cGAS/STING pathway. This is due to the lack of STING/cGAS-specific low molecular weight modulators that would be qualified for clinical exploration. The early hopes to learn from STING agonists, which have reached the clinics in recent years for selected oncology indications, have not yet materialized since the initial trials are progressing very slowly. In addition, transforming STING agonists into potent selective antagonists has turned out to be more challenging than expected. Nevertheless, there has been progress in identifying novel low molecular weight compounds, in some cases with unexpected mode of action, that might soon move to clinical trials. This study gives an overview of some of the potential indications that might profit from modulation of the cGAS/STING pathway and a short overview of the efforts in identifying STING modulators (agonists and antagonists) suitable for clinical research and describing their potential as a "drug".
cGAS-STING 通路近年来受到广泛关注，被认为是先天免疫反应的重要组成部分。自 STING 和 cGAS 被发现以来，许多基于临床前模型的观察结果表明，该通路的调节失常与许多 I 型 IFN 自身炎症性疾病有关。越来越多的证据表明，cGAS-STING 可能在经典免疫疾病之外的病理学中发挥重要作用，例如心力衰竭。已经证明，导致 STING 激活或影响 cGAS 活性的人类基因突变是导致影响幼儿和年轻成年人的罕见干扰素病的驱动因素。然而，临床上尚无调节 cGAS-STING 通路的治疗益处的数据。这是由于缺乏 STING/cGAS 特异性的低分子量调节剂，无法进行临床探索。近年来，一些具有特定肿瘤适应证的 STING 激动剂已进入临床，人们曾早期希望从这些激动剂中获得启示，但最初的试验进展非常缓慢，这一希望尚未实现。此外，将 STING 激动剂转化为有效的选择性拮抗剂比预期的更具挑战性。尽管如此，在确定新型低分子量化合物方面已经取得了进展，在某些情况下，其作用模式出人意料，这些化合物可能很快会进入临床试验。本研究概述了一些可能受益于 cGAS-STING 通路调节的潜在适应证，并简要概述了识别适合临床研究的 STING 调节剂（激动剂和拮抗剂）的工作，并描述了它们作为“药物”的潜力。
