Discovery of cGAS Inhibitors for Interferon-Driven Autoimmune Diseases

发现用于治疗干扰素驱动的自身免疫性疾病的 cGAS 抑制剂

基本信息

批准号：
10349593
负责人：
Robert G Lowery
金额：
$ 83.24万
依托单位：
BELLBROOK LABS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349593
关键词：
Active Sites African American Animal Model Apoenzymes Autoantibodies Autoimmune Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biochemical Biological Assay Biological Availability Blood Brain Cause of Death Cell Cycle Cell Death Cell Line Cell Membrane Permeability Cells Cessation of life Chronic Clinical Clinical Trials Collaborations Complex Crystallization Cutaneous Cyclic Nucleotides DNA Data Detection Dinucleoside Phosphates Drug Targeting Enzymes Exposure to Gene Expression Guanosine Triphosphate Head Heart Hispanic Human Immune Immune response Infiltration Inflammatory Innate Immune Response Interferon Type I Interferon-alpha Interferon-beta Interferons Investigation Kidney Knock-out Lead Ligands Lung Lupus Medical Modeling Molecular Molecular Conformation Molecular Weight Monitor Mus Nucleic Acids Oral Oral Administration Organ Pain Pathology Pathway interactions Patients Periodicity Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phase I Clinical Trials Photosensitivity Physiological Production Property Proteins Reporting Research Rheumatoid Arthritis Rheumatology Safety Second Messenger Systems Ships Signal Induction Signal Transduction Skin Small Business Innovation Research Grant Stimulator of Interferon Genes Structure Sunlight Symptoms Systemic Lupus Erythematosus T-Cell Activation Testing Therapeutic Therapeutic Intervention Time Tissues UV induced Universities Washington Woman Work animal efficacy antagonist autocrine belimumab common symptom curative treatments cytokine dimer drug candidate drug development ds-DNA efficacy evaluation efficacy study improved in vivo inhibitor innovation lead optimization microbial monocyte monomer mortality mouse model paracrine pathogenic microbe premature receptor residence response scaffold sensor small molecule

项目摘要

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.

概括我们正在开发环 GAMP 合酶 (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，是第二常见的疾病仅次于类风湿性关节炎的自身免疫性疾病；仅在美国就有至少 300,000 名患者健康状况良好全球超过一百万。未满足的医疗需求是巨大的：狼疮患者的患病率增加了 67% 50%的病例因主要器官受损而死亡；例如，心脏、肺、肾和脑；狼疮是 2011 年至 2015 年美国年轻非裔美国人和西班牙裔女性的第五大死因。狼疮尚无治愈方法，过去 50 年来只有一种药物（Benlysta）获得批准。狼疮病理学是由 I 型干扰素 (IFN) 和免疫传感器、环状 GAMP 合酶驱动的 (cGAS) 是 I 型 IFN 诱导的触发因素。来自垂死细胞的 DNA 与催化失活的 cGAS 结合形成一种激活的复合物，触发独特的环核苷酸第二信使环 GAMP 的产生（cGAMP）。 cGAMP 与 STING 蛋白结合诱导 I 型 IFN 的表达，具有自分泌和旁分泌导致 T 细胞和 B 细胞激活以及自身抗体产生的效应，从而引发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 HTS 测定，我们发现了两种有前途的 cGAS 拮抗剂化学型（40783 和 50101）通过不同的机制起作用并取得了实质性进展提高其生化和细胞效力，同时保持 ADME 特性，预测良好的口腔效果生物利用度。我们的结构数据表明 40783 化学型具有变构结合特性，并且可能稳定非活性 cGAS 构象，我们将在第二阶段利用这些特性来开发高度具有长停留时间的选择性先导分子。 50101 化学型似乎特异性结合超敏 cGAS-Mn-DNA 复合物，这可能会改善治疗窗口。在第二阶段我们建议：1) 进一步优化两种化学型的效力、选择性和 ADME 特性，2) 测试它们的紫外线诱导光敏性创新模型的功效，该模型复制了系统性红斑狼疮病理学的关键方面与我们的临床策略紧密结合。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系主任，开发了小鼠光敏模型并开创了 cGAS/STING 通路参与狼疮的研究。大多数研究性狼疮药物都针对 I 型干扰素的下游效应，这一策略类似于堵塞正在下沉的船上的漏洞。开发针对 cGAS 的药物，cGAS 是疾病的上游分子触发因素核酸驱动的 I 型 IFN 产生可能会彻底改变狼疮的治疗以及越来越多的 cGAS- 驱动自身免疫和炎症状况。