Optimizing virtual hits of human CGAS inhibitors to treat neurodegeneration

优化人类 CGAS 抑制剂的虚拟命中来治疗神经退行性疾病

• 批准号: 10603818
• 负责人: Li Gan
• 金额: $ 49.95万
• 依托单位: AETON THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603818
• 关键词: Ablation; Affect; Alzheimer' s Disease; Alzheimer' s disease therapeutic; American; Amyloid beta-Protein; Binding; Biological Assay; Biological Markers; Brain; Cells; Chronic; Cognitive deficits; Collaborations; Contracts; Coupling; Cyclic GMP; Cytosol; DNA; Data; Dementia; Development; Disease; Docking; Drug Kinetics; Exhibits; Future; Genetic; Genetic study; Genomics; Goals; Guanosine Triphosphate; Healthcare; Hippocampus; Human; Human Genetics; Impaired cognition; In Vitro; Inflammatory; Innate Immune Response; Interferon-beta; Interferons; Late Onset Alzheimer Disease; Lead; Ligands; Link; Liver Microsomes; Long-Term Care; Maximum Tolerated Dose; Mediating; Medicine; Metabolic; Microglia; Mitochondria; Modeling; Mus; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Organoids; Pathologic; Pathology; Pathway interactions; Pattern recognition receptor; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Preparation; Production; Property; Proteins; Quality of life; Quantitative Structure-Activity Relationship; Research Contracts; Risk; Role; STING agonists; Safety; Senile Plaques; Series; Services; Stimulator of Interferon Genes; Structure; Synapses; TBK1 gene; Tauopathies; Therapeutic; Therapeutic Effect; Toxic effect; Toxicology; Wild Type Mouse; amyloid formation; analog; clinical candidate; cost estimate; cytotoxicity; design; drug discovery; high throughput screening; hospice environment; human old age (65+); hyperphosphorylated tau; improved; in silico; in vitro activity; in vivo; induced pluripotent stem cell; inhibitor; lead candidate; meter; mouse model; nanomolar; neuroinflammation; neurotoxic; novel; novel therapeutic intervention; novel therapeutics; overexpression; pathogen; payment; programs; recruit; response; tau Proteins; tau mutation; tau-1; virtual

Abstract Aeton Therapeutics is developing inhibitors of cGAS (cyclic GMP-AMP synthase)—a pattern recognition receptor that activates STING and results in the production of interferon (IFN)-β—as novel therapies for the treatment of Alzheimer’s disease (AD). AD is the most common form of late-onset dementia and affects nearly 50 million people worldwide and an estimated 5.7 million Americans. In 2020, total payments for healthcare, long‐term care, and hospice services for people aged 65 and older with dementia were estimated to be $305 billion. The cognitive decline associated with AD correlates with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Aeton Therapeutics seeks to produce a novel therapeutic for AD by developing cGAS inhibitors (cGASi’s). cGAS is a cytosolic DNA sensing protein that has been linked to a number of neurodegenerative and inflammatory diseases. Upon sensing DNA in the cytosol (due to the presence of pathogens, genomic/mitochondrial damage, or other pathological mechanisms), cGAS catalyzes ATP/GTP coupling to produce 2’3’-cGAMP, a potent ligand of STING, resulting in the production of IFN-β. Previous studies suggest that cGAS is aberrantly activated in a tauopathy mouse model, resulting in an IFN response and neurotoxic chronic neuroinflammation. In contrast, genetic ablation of cGAS in PS19 mice, which overexpress P301S mutant tau and develop tau pathology and cognitive deficits, protects against those cognitive deficits and the loss of hippocampal synapses. These findings strongly support the development of cGASi’s to protect against the negative effects of cGAS-STING hyperactivation, but existing compounds exhibit only modest potency in inhibiting the cGAS-STING pathway in human THP1 myeloid cells. To develop novel cGASi’s to treat tau-mediated neurodegeneration in AD, in this Phase I project, Aeton Therapeutics proposes the following aims: Aim 1. Develop potent h-cGASi’s via medicinal chemistry of virtual hits 1 and 2. We have identified promising hits via a virtual screen. We will perform optimization and in vitro assessment of h- analogs to identify lead candidates. Aim 2. Determine PK, target engagement, and efficacy of h-cGASi’s in human iPSC-derived microglia and organoid model. The two best leads showing high brain exposure will be assessed in PK studies in wild-type mice and evaluated in human iPSC-derived microglia and organoids. Lead h-cGASi’s must reduce key biomarkers, such as Cxcl4, Ifnb, and TBK1/pTBK1. We expect to identify at least one lead h-cGASi that reduces key biomarkers in cells and organoids, is brain permeable, shows no toxicity in mice, and does not have off-target effects. This will lead to development of novel cGASi’s that are likely to reprogram toxic microglial responses and protect against tau-related cognitive decline.

摘要 Aeton Therapeutics正在开发cGAS（环状GMP-AMP合成酶）的抑制剂-一种模式识别受体 其激活STING并导致产生干扰素（IFN）-β-，作为治疗 阿尔茨海默病（AD）。AD是迟发性痴呆症最常见的形式，影响近5000万人 全世界大约有570万美国人。2020年，医疗保健的长期支付总额 65岁及以上痴呆症患者的护理和临终关怀服务估计为3050亿美元。的 与AD相关的认知功能下降与β淀粉样蛋白（Aβ）斑块和神经胶质瘤的形成相关。 大脑中由过度磷酸化的tau蛋白组成的缠结。Aeton Therapeutics试图制作一部小说 通过开发cGAS抑制剂（cGASi）治疗AD。cGAS是一种细胞质DNA传感蛋白，具有 与许多神经退行性疾病和炎症性疾病有关。当感应到细胞质中的DNA时 (due病原体的存在、基因组/线粒体损伤或其他病理机制），cGAS 催化ATP/GTP偶联以产生2 '3'-cGAMP，其为STING的有效配体，导致产生 IFN-β。先前的研究表明，cGAS在tau蛋白病小鼠模型中被异常激活，从而导致 干扰素反应和神经毒性慢性神经炎症。相比之下，PS19小鼠中cGAS的基因消融， 其过度表达P301 S突变tau并发展tau病理和认知缺陷， 认知缺陷和海马突触的丧失。这些发现强烈支持了 cGASi’s来保护免受cGAS-STING超活化的负面影响，但现有的化合物表现出 在抑制人THP 1骨髓细胞中的cGAS-STING途径方面仅具有中等效力。开发新 cGASi治疗AD中tau介导的神经变性，在这个I期项目中，Aeton Therapeutics提出 目标：目标1。通过虚拟命中1和2的药物化学开发有效的h-cGASi。我们 已经通过虚拟屏幕确定了有希望的命中。我们将进行优化和体外评估的h- 类似物来识别主要候选人。目标2.确定h-cGASi在以下患者中的PK、靶标接合和功效： 人iPSC衍生小胶质细胞和类器官模型。两个最好的线索显示高大脑暴露将是 在野生型小鼠的PK研究中评估，并在人iPSC衍生的小胶质细胞和类器官中评估。铅 h-cGASi必须减少关键的生物标志物，如Cxcl 4、Ifnb和TBK 1/pTBK 1。我们希望至少能找出 一种减少细胞和类器官中关键生物标志物的铅h-cGASi是脑渗透性的，在 小鼠，并且没有脱靶效应。这将导致开发新的cGASi， 重新编程毒性小胶质细胞反应，并防止tau相关的认知能力下降。