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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：
10617321
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/10617321
关键词：
ABCB1 gene Ablation Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein 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 Generations Genes Genetic Genetic study Gliosis Goals Guanosine Triphosphate Hippocampus 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 Microsomes 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 Viral Wild Type Mouse analog 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 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

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.

抽象的阿尔茨海默病（AD）是老年人最常见的痴呆症。 β 淀粉样蛋白 (Aβ) 和 tau 蛋白病理学和神经炎症是阿尔茨海默病的三个主要特征。绝大多数药物发现过去几十年的努力主要集中在针对 Aβ 病理学，但临床试验均未取得成功。虽然 tau 病理学而非 Aβ 病理学在 AD 记忆衰退中发挥着关键作用，但药物针对 tau 对神经元的直接影响也没有取得成功。引人注目的人类遗传学研究将先天免疫反应与罹患迟发性 AD 的风险升高联系起来，支持针对小胶质细胞，大脑中常驻的免疫细胞，作为 AD 的下一代治疗方法。我们表明了关键作用环 GMP-AMP 合酶 (cGAS) - 小胶质细胞毒性和干扰素基因 (STING) 信号传导的刺激剂 tau 介导的认知能力下降。 cGAS（一种主要的胞质 dsDNA 传感器）的激活可催化产生 cGAMP 是一种极其有效的 STING 激动剂，作为激活 cGAS-STING 通路的第二信使，通过激活干扰素调节因子（IRF）产生抗病毒反应，细胞因子和 I 型干扰素基因的表达。我们发现部分或完全的基因 cGAS 消融防止 PS19 Tau 小鼠中 tau 介导的空间学习和记忆缺陷。此外，治疗使用 cGAS 小分子抑制剂可减少干扰素反应，减少小胶质细胞增生，并保护对抗患有 tau 蛋白病的 AD 小鼠模型中的认知缺陷。我们假设抑制 cGAS 活性将抑制神经炎症和适应不良的免疫反应，防止 AD 相关的缺陷。我们建议开发小分子人类 cGAS (h-cGAS) 抑制剂作为治疗 AD 的新型小胶质细胞调节剂。在目标 1 中，我们将从两个已知的命中开始开发先导 h-cGAS 抑制剂，并确定这些抑制剂是否抑制剂在无细胞和细胞检测中有效调节 cGAS-STING 通路。我们期望确定通过点击扩展和合成 > 200 个类似物来获得新的点击。目标 2 侧重于有效的类似物优化 cGAS 抑制剂 TDI-6570 是一种领先的低纳摩尔有效小鼠 cGAS (m-cGAS) 抑制剂，具有 h-cGAS 活性降低 10 倍。我们将设计多达 50 个新的类似物。 SAR、对接实验和in-的结果将使用计算机计算来最大限度地提高潜在客户的质量。完成目标 1 和目标 2 将领先 5 用于体内和功效研究的化合物。在目标 3 中，我们将确定 h-cGAS 抑制剂在 tau蛋白病小鼠模型，以及对人类干细胞衍生的小胶质细胞和脑类器官的功效 tau蛋白病。在拟议的 5 年研究结束时，我们预计会确定 1-2 种领先的 h-cGAS 抑制剂作为工具化合物和原理证明，以进一步推进作为治疗阿尔茨海默病的候选药物和相关的神经系统疾病。