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.

概括我们正在开发小分子拮抗剂以鉴定候选药物的环状GAMP合酶（CGA）狼疮分子。系统性红斑狼疮（SLE）或简单的狼疮是第二常见的类风湿关节炎旁边的自身免疫性疾病；仅在美国，至少有300,000名患者全球超过一百万。未满足的医疗需求是巨大的：狼疮患者增加了67％在50％的病例中，死亡率对主要器官损坏；例如，心脏，肺，肾脏和大脑；狼疮是 2011年至2015年，美国年轻的非裔美国人和西班牙裔妇女的第五大死亡原因。在过去的50年中，没有治疗狼疮的治疗方法，只有一种药物（Benlysta）得到了批准。狼疮病理是由I型干扰素（IFN）和免疫传感器循环GAMP合酶驱动的（CGA）是I型IFN诱导的触发器。垂死细胞中的DNA与催化无效的CGA结合形成活化的复合物，触发独特的环状核苷酸第二信使的产生（CGAMP）。 CGAMP与刺激蛋白结合以诱导I型IFN的表达，并用自分泌和旁分泌诱导导致T-和B细胞激活以及自动抗体产生的影响，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HTS测定法，我们发现了两个有前途的CGA 通过不同机制起作用的拮抗剂化学型（40783和50101），并取得了重大进步增加其生化和细胞效力，同时保持良好口服的ADME特性生物利用度。我们的结构数据表明40783化学型具有变构结合特性，可能稳定不活动的CGA构象，我们将在II阶段中利用这些构象来发展高度选择性铅分子的停留时间很长。 50101化学型似乎与A特别结合高敏的CGAS-MN-DNA复合物，这可能会导致改善的治疗窗口。在第二阶段我们提议：1）进一步优化两种化学型的效力，选择性和ADME特性，2）测试其紫外线诱导的光敏性的创新模型中的功效，复制了SLE病理的关键方面与我们的临床策略紧密一致。动物功效研究将与基思·埃尔肯（Keith Elkon）合作进行西雅图华盛顿大学风湿病学负责人，他开发了鼠标光敏模型和是否开创了有关狼疮中CGA/STING途径参与的研究。大多数研究狼疮药物的目标是I型IFN的下游影响，这种策略类似于在沉没的船上堵塞孔。靶向CGA的药物的开发，这是上游分子触发的核酸驱动的I型IFN产生可以彻底改变狼疮的处理，并越来越多的CGAS- 驱动的自身免疫和炎症条件。