cGAS inhibitors for Alzheimer's disease treatment

用于治疗阿尔茨海默病的 cGAS 抑制剂

基本信息

批准号：
10316803
负责人：
Li Gan
金额：
$ 84.75万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316803
关键词：
ABCB1 gene Ablation Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Antiviral Agents Antiviral Response Behavior Biochemical Biological Biological Assay Brain Cells Cerebrum Chronic Clinical Trials Cognitive deficits Coupling Cyclic GMP DNA Dementia Development Disease Docking Drug Kinetics Drug Targeting Elderly Evaluation Exhibits Gene Proteins Generations Genes Genetic Genetic study Goals Guanosine Triphosphate Hippocampus (Brain)Histology Human Human Genetics Immune Immune response Impaired cognition In Vitro Inflammatory Innate Immune Response Interferon Activation Interferon Type I Interferon-beta Interferons Late Onset Alzheimer Disease Lead Learning Ligands Link Liver Liver Microsomes Measures Mediating Memory Loss Memory impairment Metabolic Metabolism Microglia Modeling Mus Myelogenous Myeloid Cells Neurofibrillary Tangles Neurons Organoids Pathologic Pathology Pathway interactions Permeability Pharmaceutical Preparations Phase Plasma Play Preclinical Testing Production Property Proteins Risk Role Screening Result Second Messenger Systems Senile Plaques Signal Transduction Source Stimulator of Interferon Genes Structure Structure-Activity Relationship Synapses Tauopathies Tissues Toxic effect Wild Type Mouse analog base behavior test beta amyloid pathology cytokine design drug candidate drug discovery ds-DNA efficacy study experimental study human stem cells hyperphosphorylated tau improved in silico in vivo in vivo evaluation inhibitor/antagonist luminescence mouse model nanomolar nervous system disorder neuroinflammation neurotoxic next generation novel novel lead compound overexpression preclinical study preference protective effect response risk variant sensor small molecule small molecule inhibitor success tau Proteins tau mutation therapeutic target tool transcriptomics

ABCB1 gene Ablation Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Antiviral Agents Antiviral Response Behavior Biochemical Biological Biological Assay Brain Cells Cerebrum Chronic Clinical Trials Cognitive deficits Coupling Cyclic GMP DNA Dementia Development Disease Docking Drug Kinetics Drug Targeting Elderly Evaluation Exhibits Gene Proteins Generations Genes Genetic Genetic study Goals Guanosine Triphosphate Hippocampus (Brain)Histology Human Human Genetics Immune Immune response Impaired cognition In Vitro Inflammatory Innate Immune Response Interferon Activation Interferon Type I Interferon-beta Interferons Late Onset Alzheimer Disease Lead Learning Ligands Link Liver Liver Microsomes Measures Mediating Memory Loss Memory impairment Metabolic Metabolism Microglia Modeling Mus Myelogenous Myeloid Cells Neurofibrillary Tangles Neurons Organoids Pathologic Pathology Pathway interactions Permeability Pharmaceutical Preparations Phase Plasma Play Preclinical Testing Production Property Proteins Risk Role Screening Result Second Messenger Systems Senile Plaques Signal Transduction Source Stimulator of Interferon Genes Structure Structure-Activity Relationship Synapses Tauopathies Tissues Toxic effect Wild Type Mouse analog base behavior test beta amyloid pathology cytokine design drug candidate drug discovery ds-DNA efficacy study experimental study human stem cells hyperphosphorylated tau improved in silico in vivo in vivo evaluation inhibitor/antagonist luminescence mouse model nanomolar nervous system disorder neuroinflammation neurotoxic next generation novel novel lead compound overexpression preclinical study preference protective effect response risk variant sensor small molecule small molecule inhibitor success tau Proteins tau mutation therapeutic target tool transcriptomics

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项目摘要

ABSTRACT Alzheimer's disease (AD) is the most common form of dementia in elderly. Amyloid-β (Aβ) and tau pathologies and neuroinflammation are three major hallmarks of Alzheimer's disease. Vast majority of the drug discovery efforts in the past decades have focused on targeting the Aβ pathology, but none are successful in Clinical Trials. While tau pathology, not the Aβ pathology, has emerged to play critical role in memory decline in AD, drugs targeting the direct effects of tau on neurons also have not met success either. Compelling human genetic studies link the innate immune responses to elevated risk of developing late-onset AD, supporting targeting microglia, resident immune cells in the brain, as the next-generation treatment for AD. We showed that a critical role of cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling in microglial toxicity and tau-mediated cognitive decline. Activation of cGAS, a major cytosolic dsDNA sensor, catalyzes production of cGAMP, an extremely potent STING agonist as the second messenger that activates cGAS-STING pathway, leading to a production of the antiviral responses through activation of interferon regulatory factors (IRFs) and expression of cytokine and type I interferon genes. We found that a partial or complete genetic cGAS ablation protected against the tau-mediated spatial learning and memory deficits in PS19 Tau mice. Moreover, treatment with a small molecule inhibitor of cGAS reduces interferon responses, diminished microgliosis, and protected against cognitive deficits in an AD mouse model with tauopathy. We hypothesize that inhibitors the cGAS activity will dampen neuroinflammation and maladaptive immune responses, protect against AD-related deficit. We propose to develop small molecule human cGAS (h-cGAS) inhibitors as novel microglial modulators to treat AD. In Aim 1, we will develop lead h-cGAS inhibitors starting with two known hits and determine whether these inhibitors effectively modulate the cGAS-STING pathway in cell-free and cell-based assays. We expect to identify new hits via hits expansion and synthesize >200 analogs. Aim 2 focuses on optimization of analogs a potent cGAS inhibitor, TDI-6570, which is a lead low nanomolar potent mouse cGAS (m-cGAS) inhibitor and possesses 10x less h-cGAS activity. We will design up to 50 new analogs. Results of SAR, docking experiments, and in- silico calculation will be used to maximize the lead quality. Completion of Aim 1 and Aim 2 will lead to 5 lead compounds for in vivo and efficacy studies. In Aim 3, we will establish PK and efficacy of h-cGAS inhibitors in mouse model of tauopathy, and efficacy in human stem cell-derived microglia and cerebral organoids with tauopathy. At the end of the proposed 5 years study, we anticipate identifying 1-2 lead h-cGAS inhibitors as tool compounds and a proof of principle to further advance as drug candidates to treat Alzheimer's disease and related neurological disorders.

抽象的阿尔茨海默氏病（AD）是最常见的痴呆症形式。淀粉样蛋白-β（Aβ）和TAU病理神经炎症和神经炎症是阿尔茨海默氏病的三个主要标志。绝大多数药物发现在过去的几十年中，努力集中在靶向Aβ病理学上，但在临床试验中没有成功。虽然tau病理学，而不是Aβ病理学，在AD中的记忆下降中起着至关重要的作用靶向tau对神经元的直接影响也没有成功。引人入胜的人类遗传研究将先天免疫反应与发展后期广告的风险升高，支持针对小胶质细胞，大脑中的驻留免疫细胞是AD的下一代治疗。我们表明，环状GMP-AMP合酶（CGAS） - 小胶质毒性中的干扰素基因（STING）信号的刺激剂 tau介导的认知下降。 CGA的激活是一种主要的胞质DSDNA传感器，催化产生 CGAMP是一种极为潜在的刺痛激动剂，作为激活CGAS刺道途径的第二个使者，通过激活干扰素调节因子（IRF）和细胞因子和I型干扰素基因的表达。我们发现部分或完整的遗传CGA消融防止TAU介导的空间学习和记忆在PS19 Tau小鼠中定义。而且，治疗 CGA的小分子抑制剂减少了干扰反应，小胶质细胞增多减少并受到保护在带有tauopathy的AD小鼠模型中反对认知缺陷。我们假设抑制CGA活性会抑制神经炎症和适应不良的免疫反应，防止与广告有关的防御。我们提出开发小分子人CGA（H-CGA）抑制剂作为治疗AD的新型小胶质调节剂的建议。在AIM 1中，我们将开发铅H-CGAS抑制剂，从两个已知的命中开始，并确定这些是否是否抑制剂有效地调节了无细胞和基于细胞的测定中的CGAS刺激途径。我们希望确定通过命中率扩展和合成> 200个类似物的新命中。 AIM 2专注于优化类似物 CGAS抑制剂TDI-6570，它是铅低纳摩尔有效的小鼠CGA（M-CGAS）抑制剂，并具有 H-CGAS活性减少了10倍。我们将设计多达50个新的模拟。 SAR，对接实验和内部的结果计算机计算将用于最大化铅质量。 AIM 1和AIM 2的完成将导致5领先体内和效率研究的化合物。在AIM 3中，我们将建立PK和H-CGAS抑制剂的效率小鼠tauopathy的小鼠模型，以及人类干细胞衍生的小胶质细胞和脑类器官的效率 tauopathy。在拟议的5年研究结束时，我们预计将识别1-2个铅H-CGAS抑制剂作为工具化合物和原则证明，以进一步促进毒品候选者治疗阿尔茨海默氏病和相关的神经系统疾病。