Discovery of cGAS Inhibitors for Interferon-Driven Autoimmune Diseases

摘要 我们正在开发环磷酸腺苷合成酶(CGAS)的小分子拮抗剂，以确定候选药物 狼疮的分子。系统性红斑狼疮(SLE)，或简称狼疮，是第二常见的 自身免疫性疾病仅次于类风湿性关节炎；仅在美国就有至少30万名患者 全球超过一百万人。未得到满足的医疗需求是巨大的：狼疮患者的 死亡率与主要器官损害的比例为50%；例如心脏、肺、肾脏和脑；狼疮是 2011年至2015年，美国年轻的非裔美国人和西班牙裔女性的第五大死因。 目前还没有治愈狼疮的方法，在过去的50年里，只有一种药物(Benlysta)获得批准。 狼疮的病理是由I型干扰素(IFN)和免疫传感器环磷酸腺苷合成酶(cGAMP合成酶)驱动的 (CGAS)，是诱导I型干扰素的触发因子。垂死细胞的DNA与催化失活的cGAs结合形成 一种激活的复合体，触发产生独特的环核苷酸第二信使-环GAMP (CGAMP)。CGAMP与刺蛋白结合，通过自分泌和旁分泌诱导I型IFN的表达 导致T和B细胞激活和自身抗体产生的效应，导致细胞的恶性循环 死亡和自身免疫。 使用在单独的SBIR下开发的创新的HTS分析，我们发现了两个有前景的cGAs 通过不同机制发挥作用并已取得实质性进展的拮抗剂化学型(40783和50101) 在保持ADME预测良好口腔功能的同时提高其生化和细胞效力 生物利用度。我们的结构数据表明，40783化学类型具有变构结合性质，并可能 稳定不活跃的cGAS构象，我们将在第二阶段利用这些特性来开发高度 具有较长停留时间的选择性铅分子。50101化学类型似乎与一种 超敏cGAS-Mn-DNA复合体，可改善治疗窗口。在第二阶段，我们 建议：1)进一步优化这两种化学类型的效力、选择性和ADME性质；2)测试它们的 一种创新的紫外线诱导光敏模型的有效性，该模型复制了SLE病理和 与我们的临床战略紧密结合。动物功效研究将与Keith Elkon合作进行， 西雅图华盛顿大学风湿病学主任，他开发了小鼠光敏模型和 开创性地研究了cGAS/STING通路在狼疮发病中的作用。 大多数研究中的狼疮药物都针对I型干扰素的下游效应，这一策略类似于 堵住一艘正在下沉的船上的洞。靶向cGAS的药物的开发，上游分子触发 核酸驱动的I型干扰素的产生可能会带来狼疮治疗的革命性变化，以及越来越多的cGAs- 导致自身免疫和炎症的情况。

Summary We are developing small molecule antagonists for cyclic GAMP synthase (cGAS) to identify a candidate drug molecule for lupus. Systemic lupus erythematosus (SLE), or simply lupus, is the second most common autoimmune disease next to rheumatoid arthritis; there are at least 300,000 patients in the U.S. alone and well over a million globally. The unmet medical need is enormous: lupus patients suffer from a 67% increase in mortality rate with damage to major organs in 50% of cases; e.g., heart, lung, kidneys, and brain; lupus was the 5th leading cause of death among young African American and Hispanic women in the U.S. from 2011-2015. There are no curative treatments for lupus, and only one drug (Benlysta) has been approved in the last 50 years. Lupus pathology is driven by type I interferons (IFNs), and the immune sensor, cyclic GAMP synthase (cGAS), is the trigger for type I IFN induction. DNA from dying cells binds to catalytically inactive cGAS to form an activated complex, triggering production of a unique cyclic nucleotide second messenger, cyclic GAMP (cGAMP). cGAMP binds to the STING protein to induce expression of type I IFNs, with autocrine and paracrine effects that lead to activation of T- and B-cells and auto-antibody production, precipitating a vicious cycle of cell death and autoimmunity. Using an innovative HTS assay developed under a separate SBIR, we discovered two promising cGAS antagonist chemotypes (40783 and 50101) that function via distinct mechanisms and have made substantial progress on increasing their biochemical and cellular potency while maintaining ADME properties predictive of good oral bioavailability. Our structural data indicate that the 40783 chemotype has allosteric binding properties and may stabilize an inactive cGAS conformation, properties which we will leverage in Phase II to develop a highly selective lead molecule with a long residence time. The 50101 chemotype appears to bind specifically to a hypersensitized cGAS-Mn-DNA complex, which could lead to an improved therapeutic window. In Phase II we propose to: 1) further optimize the potency, selectivity and ADME properties of the two chemotypes and 2) test their efficacy in an innovative model for UV-induced photosensitivity that replicates key aspects of SLE pathology and aligns closely with our clinical strategy. The animal efficacy studies will be performed in collaboration with Keith Elkon, Head of Rheumatology at University of Washington, Seattle, who developed the mouse photosensitivity model and has pioneered research on the involvement of the cGAS/STING pathway in lupus. Most investigational lupus drugs target the downstream effects of type I IFNs, a strategy that is akin to plugging holes in a sinking ship. The development of drugs that target cGAS, the upstream molecular trigger for nucleic-acid driven type I IFN production could revolutionize the treatment of lupus along with a growing list of cGAS- driven autoimmune and inflammatory conditions.