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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

抽象的 Aeton Therapeutics正在开发CGA（环状GMP-AMP合酶）的抑制剂 - 一种模式识别受体激活刺痛并导致干扰素（IFN）-β的产生，作为治疗的新疗法阿尔茨海默氏病（AD）。广告是晚期痴呆症的最常见形式，影响近5000万全球人，估计有570万美国人。 2020年，医疗保健总付款护理和65岁以上患有痴呆症患者的临终关怀服务估计为3050亿美元。与AD相关的认知下降与淀粉样β（Aβ）斑块和神经原纤维的形成相关由大脑中的高磷酸化tau组成的缠结。 Aeton Therapeutics试图制作小说通过开发CGAS抑制剂（CGASI）的AD治疗。 CGA是一种胞质DNA感应蛋白，已有我们与许多神经退行性疾病和炎症性疾病有关。在感测DNA时在细胞质中（由于存在病原体，基因组/线粒体损伤或其他病理机制），CGA 催化ATP/GTP耦合产生2'3'-cgamp，这是一种潜在的刺激配体，导致产生 IFN-β。先前的研究表明，CGA在Tauopathy小鼠模型中异常激活，从而导致 IFN反应和神经毒性慢性神经炎症。相反，PS19小鼠中CGA的遗传消融，过表达P301S突变体tau并发展出tau病理学和认知定义，可预防那些认知缺陷和海马突触的丧失。这些发现强烈支持 CGASI可以防止CGAS-sting过度激活的负面影响，但现有化合物展示仅在抑制人Thp1髓样细胞中的CGAS刺途径时适度的效力。发展小说 CGASI在此阶段I项目Aeton Therapeicts提案中治疗AD中的Tau介导的神经变性以下目的：目标1。通过虚拟命中1和2的药物化学发展潜在的H-CGASI。已经通过虚拟屏幕确定了Promise Hits。我们将对H-进行优化和体外评估识别主要候选人的类似物。目标2。确定H-CGASI的PK，目标参与和效率人IPSC衍生的小胶质细胞和器官模型。表现出高脑暴露的两个最佳线索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进行了评估。带领 H-CGASI必须减少关键生物标志物，例如CXCL4，IFNB和TBK1/PTBK1。我们希望至少确定一个降低细胞和器官中关键生物标志物的铅H-CGASI是可渗透的，在小鼠，并且没有脱靶效应。这将导致新颖的CGASI的发展重编程有毒的小胶质细胞反应并防止与TAU相关的认知下降。