Development of PU.1 Inhibitory Modulators as Novel Therapeutics for Alzheimer's Disease

项目概要/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种致命的神经退行性疾病，全球患病率接近5000万 预计到2040年将翻一番。找到有效的治疗AD已被证明是困难的， 许多备受瞩目的3期临床试验失败证明了这一点，其中大多数直接针对减少 淀粉样蛋白。因此，开发新的药物策略来对抗AD变得越来越迫切。 药物成功谈判药物开发管道并获得FDA批准的可能性是其他药物的两倍， 它们的目标得到了人类疾病基因研究的支持。人类基因研究显示， 小胶质细胞参与阿尔茨海默病进展的关键作用，最近发现 转录因子PU.1是小神经胶质细胞在发育过程中采用的促神经退行性表型的驱动因子。 衰老和疾病因此，该提案旨在开发新发现的新型PU.1抑制性调节剂 （PIM）用于临床前开发，长期目标是在临床上测试减少PU的假设。 在高危人群中，小胶质细胞的活性将安全地延迟AD发病年龄（AAO）。 该提案中的研究利用了神经变性联盟的跨学科结构， 基础科学研究人员和行业药物开发资深人士之间的独特合作 根据一项合作协议，推动旨在治疗阿尔茨海默病的新疗法， 其他神经退行性疾病。根据具体目标1，将评估PIM的体内安全性和有效性 在AD的小鼠模型中测定。在具体目标2下，将进行平行目标交战研究 确定PIM的靶点，并将确定的靶点用于开发测定疗效的试验 在AD和离体模型中的PIM。在具体目标3下，将使用PK/PD优化选定的PIM， ADMET筛选，将先导工具化合物开发为适合未来I期研究的候选化合物。 神经退行性疾病联盟的生物学、化学和药理学专业知识， 德克萨斯大学MD安德森癌症中心、马萨诸塞州理工学院和麻省理工学院。 西奈医学院，使这组研究人员非常适合执行提出的目标。

Project Summary/Abstract Alzheimer's disease (AD) is a fatal neurodegenerative disease with a global prevalence close to 50 million people, which is expected to double by 2040. Finding an effective treatment for AD has proven difficult, as evidenced by numerous high profile Phase 3 clinical trial failures, most of which directly target the reduction of ß-amyloid. Thus, it is becoming increasingly urgent to develop new pharmacological strategies to combat AD. Drugs are twice as likely to successfully negotiate the drug development pipeline and obtain FDA approval when their targets are supported from human genetic studies of disease. Human genetic studies have revealed a critical role for microglia involvement in Alzheimer’s disease progression, and it has recently been discovered that the transcription factor PU.1 is a driver of the pro-neurodegenerative phenotype adopted by microglia during aging and disease. This proposal therefore aims to develop novel, newly-discovered PU.1 Inhibitory Modulators (PIMs) for preclinical development, with the long term goal of clinically testing the hypothesis that reducing PU.1 activity in microglia will safely delay the age of AD onset (AAO) in at-risk populations. The studies in this proposal leverage the interdisciplinary structure of the Neurodegeneration Consortium, a unique collaboration between basic science researchers and industry drug development veterans operating under a collaborative agreement to push forward novel therapeutics aimed at treating Alzheimer’s diseaes and other neurodegenerative diseases. Under Specific Aim 1, the in vivo safety and efficacy of PIMs will be determined in mouse models of AD. Under Specific Aim 2, parallel target engagement studies will be performed to identify the target of PIMs, and the identified targets will be used to develop assays to determine the efficacy of PIMs in AD and in ex vivo models. Under Specific Aim 3, selected PIMs will be optimized using PK/PD and ADMET screening to develop lead tool compounds into candidate compounds suitable for future Phase I studies. The combined biology, chemistry, and pharmacology expertise in the Neurodegeneration Consortium, spanning The University of Texas MD Anderson Cancer Center, the Massachussets Institute of Technology, and the Mt. Sinai School of Medicine, make this group of researchers ideally suited to execute the proposed aims.