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Small molecule inhibitors of hyperphosphorylated tau aggregation and cytotoxicity for the development of Alzheimer’s therapeutics

过度磷酸化 tau 聚集和细胞毒性的小分子抑制剂，用于开发阿尔茨海默病疗法

基本信息

批准号：
10488198
负责人：
Jessica Fortin
金额：
$ 18.17万
依托单位：
PURDUE UNIVERSITY
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：
2021-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10488198
关键词：
ADME Study Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Alzheimer’s disease biomarker Amyloid beta-Protein Animals Appearance Autopsy Award Binding Blood - brain barrier anatomy Brain Cell Death Cells Chemistry Clinical Clinical Trials Cysteine Cytoprotection Data Development Disease Dose Drug Screening Drug Targeting Exhibits Failure Funding Funding Opportunities Future Health Impaired cognition In Vitro Inclusion Bodies Injections Lead Libraries Link Metabolism Methods Modeling Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neurofibrillary Tangles Neurons Outcome Pathology Permeability Pharmaceutical Preparations Pharmacology Phenotype Play Preventive Program Development Property Protein Isoforms Proteins Recombinants Resveratrol Role Senile Plaques Solid Solubility Symptoms Tauopathies Technology Testing Therapeutic Toxic effect United States National Institutes of Health abnormally phosphorylated tau absorption base biophysical techniques cytotoxic cytotoxicity drug development drug discovery effective therapy follow-up high throughput screening high-throughput drug screening hyperphosphorylated tau inhibitor inorganic phosphate monomer neuron loss neuroprotection neurotoxic novel novel strategies pharmacokinetics and pharmacodynamics preclinical study prevent small molecule small molecule inhibitor spatiotemporal tau Proteins tau aggregation tau-1

项目摘要

PROJECT SUMMARY Neurodegeneration in Alzheimer's disease (AD) is increasingly accepted to result from the toxicity of hyperphosphorylated tau aggregates, the major constituent of the neurofibrillary tangles (NFTs) in the brains of AD patients. The vast majority of AD drug development efforts have focused on inhibiting or clearing Aβ plaques. So far, these efforts have failed in clinical trials. In contrast to Aβ plaques, which poorly correlate with progression of clinical AD symptoms, the spatiotemporal distribution of NFTs cognitive impairment. Mounting evidence suggests that pre-tangle aggregates of hyperphosphorylated tau are toxic to neurons, and likely play a key role in AD neurodegeneration. Thanks to a technology for generating phosphorylated proteins called PIMAX, this project will be the first to screen drugs for inhibition of aggregation of hyperphosphorylated tau (hyper-p-tau). Until now, hyper-p-tau in sufficient quantities to screen a compound library has been unavailable. Previous projects screened compounds for binding either unphosphorylated tau, or tau's two cysteine groups, or tau with only 1 to 3 phosphates. As our PIMAX-generated hyper-p-tau drug target, we will use tau isoform 1N4R phosphorylated on up to 16 aa residues. In brains of AD patients, tau 1N4R is hyperphosphorylated, and 8 of these 16 residues are used to stage AD postmortem brains. Thus, due to our unique hyperphosphorylated target, this project does not duplicate previous drug projects targeting tau, and is instead a groundbreaking new approach to discovering inhibitors of tau aggregation into neurotoxic fibrils. Our preliminary data shows that our novel small molecules (JF compounds) can inhibit aggregation of hyper-p-tau 1N4R. Our most potent inhibitor to date, JF-19-73, dose- dependently antagonizes oligomer formation and neuronal cytotoxicity of hyper-p-tau 1N4R in vitro, suggesting its potential for neuroprotection. JF-19-73 is more potent than resveratrol in inhibiting hyper-p-tau 1NR4 aggregation. JF compounds have classic drug attributes (Rules of Five by Lipinski et al.), exhibit positive predictive scores to traverse the blood-brain barrier, and are non-toxic to cells. Aim 1 will optimize JF chemistry for solubility (e.g. reduction of ClogP), inhibition of formation of cytotoxic hyper- p-tau 1N4R oligomeric fibrils, and cytoprotection in vitro. Aim 2 will test the most potent hyper-p-tau aggregation inhibitors for ADME properties in vitro and identify JF lead compounds for future preclinical studies including animal and PK/PD studies. Overall Impact: Neurodegeneration in AD is increasingly accepted to result from the toxicity of hyperphosphorylated tau aggregates. This project will enable us to move into a lead development program with optimized JF derivatives that target hyperphosphorylated tau — the form of tau actually found in postmortem brains of AD patients. This project is unique because it is based on overcoming a longstanding critical barrier in tau pharmacology — lack of hyperphosphorylated tau in sufficient quantities for high throughput screening.

项目概要越来越多的人认为阿尔茨海默氏病 (AD) 的神经退行性疾病是由以下物质的毒性引起的：过度磷酸化的 tau 蛋白聚集体，是大脑中神经原纤维缠结 (NFT) 的主要成分 AD患者。绝大多数 AD 药物开发工作都集中在抑制或清除 Aβ 斑块上。到目前为止，这些努力在临床试验中都失败了。与 Aβ 斑块相比，Aβ 斑块与进展相关性较差临床 AD 症状、NFT 认知障碍的时空分布。越来越多的证据表明过度磷酸化 tau 蛋白的预缠结聚集体对神经元有毒，并且可能发挥关键作用在 AD 神经变性中。得益于一种名为 PIMAX 的磷酸化蛋白质生成技术，该项目将成为第一个筛选抑制过度磷酸化 tau (hyper-p-tau) 聚集的药物。到目前为止，hyper-p-tau 尚未获得足够的数量来筛选化合物库。之前的项目筛选了化合物用于结合未磷酸化的 tau、或 tau 的两个半胱氨酸基团、或仅具有 1 至 3 个磷酸基团的 tau。作为我们 PIMAX 生成的 hyper-p-tau 药物靶点，我们将使用最多 16 个氨基酸磷酸化的 tau 亚型 1N4R 残留物。在 AD 患者的大脑中，tau 1N4R 过度磷酸化，这 16 个残基中的 8 个用于 AD阶段死后大脑。因此，由于我们独特的过度磷酸化靶标，该项目不会重复之前针对 tau 的药物项目，而是一种发现 tau 抑制剂的突破性新方法 tau 蛋白聚集成神经毒性原纤维。我们的初步数据表明，我们的新型小分子（JF 化合物）可以抑制 hyper-p-tau 1N4R 的聚集。我们迄今为止最有效的抑制剂，JF-19-73，剂量- 体外依赖地拮抗 hyper-p-tau 1N4R 的寡聚体形成和神经元细胞毒性，表明其神经保护潜力。 JF-19-73 比白藜芦醇抑制 hyper-p-tau 1NR4 更有效聚合。 JF 化合物具有经典的药物属性（Lipinski 等人的五规则），表现出积极的作用预测分数穿过血脑屏障，并且对细胞无毒。目标 1 将优化 JF 化学的溶解度（例如 ClogP 的减少）、抑制细胞毒性高毒性物质的形成 p-tau 1N4R 寡聚原纤维和体外细胞保护。目标 2 将测试最有效的 hyper-p-tau 聚集体外 ADME 特性抑制剂，并确定 JF 先导化合物用于未来的临床前研究，包括动物和 PK/PD 研究。总体影响：AD 中的神经变性越来越被认为是由过度磷酸化 tau 聚集体的毒性。该项目将使我们能够进入领先开发阶段具有针对过度磷酸化 tau 的优化 JF 衍生物的程序——tau 的形式实际上存在于 AD 患者死后的大脑。该项目是独一无二的，因为它基于克服长期存在的问题 tau 药理学的关键障碍 — 缺乏足够数量的过度磷酸化 tau 以实现高通量筛选。