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.

项目摘要阿尔茨海默氏病（AD）中的神经变性越来越被接受，因此是由于毒性而引起的高磷酸化的tau聚集体，主要构成神经原纤维缠结（NFT）的大脑广告患者。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已经失败。与Aβ斑块相反，与进展相关的Aβ斑块临床AD症状，NFTS认知障碍的空间时间分布。越来越多的证据表明高磷酸化tau的预曲骨骨料对神经元有毒，并且可能起关键作用在AD神经变性中。感谢您生成称为PIMAX的磷酸化蛋白质的技术，该项目将是第一个筛查药物以抑制高磷酸化tau（超p-tau）的聚集。到目前为止，Hyper-p-tau 筛选复合库的足够数量是不可用的。以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个磷酸盐的tau。作为我们的PIMAX生成的高-P-TAU药物靶标，我们将使用多达16个AA的Tau同工型1N4R磷酸化残留物。在AD患者的大脑中，Tau 1N4R被过度磷酸化，其中16个残基中有8个用于阶段广告后大脑。这是由于我们独特的热磷酸化目标，该项目不会重复以前针对tau的药物项目，而是一种开创性的新方法，以发现发现的抑制剂 TAU聚集到神经毒性原纤维中。我们的初步数据表明我们的新型小分子（JF）化合物）可以抑制高-P-TAU 1N4R的聚集。我们迄今为止最有效的抑制剂JF-19-73，剂量 - 在体外，依赖性地拮抗了高P-TAU 1N4R的寡聚体形成和神经元细胞毒性，这表明它的神经保护潜力。 JF-19-73比白藜芦醇在抑制Hyper-P-TAU 1NR4方面更有潜力聚合。 JF化合物具有经典的药物属性（Lipinski等人的五规则），暴露了阳性预测分数遍历血脑屏障，对细胞无毒。 AIM 1将优化JF化学的溶解度（例如，降低ClOGP），抑制细胞毒性高 - 形成 p-tau 1N4R低聚原纤维和体外细胞保护。 AIM 2将测试最有效的Hyper-P-TAU聚合体外ADME性质的抑制剂，并确定JF铅化合物的未来临床前研究动物和PK/PD研究。总体影响：AD中的神经变性越来越被接受，从高磷酸化的tau聚集体的毒性。该项目将使我们能够进入领先的发展具有优化的JF衍生物的程序，靶向热磷酸化的tau - 在 AD患者的后大脑。该项目是独一无二的 tau药理学的关键障碍 - 缺乏足够量的高磷酸化tau来实现高通量筛选。