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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：
10258171
负责人：
Robert G Lowery
金额：
$ 98.88万
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 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258171
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 Hispanics 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 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 autocrine belimumab common symptom curative treatments cytokine dimer drug candidate drug development ds-DNA efficacy evaluation efficacy study improved in vivo inhibitor/antagonist 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.

总结