Identification and Development of Tau-Lowering Small-Molecule Drugs

项目摘要 我们的目标是识别或产生小分子，安全有效地降低大脑微管水平- 相关蛋白tau（MAPT），并可开发成治疗阿尔茨海默病（AD）和其他疾病的药物。 tau蛋白病，其中tau蛋白导致神经变性和认知下降。由于tau也使 其它AD相关蛋白的致病作用（例如，Aβ和apoE 4），降低tau水平可减轻其作用 这种多因素疾病的多个驱动因素，并提供比其他单一疗法更有效的治疗 在临床试验中失败了。在小鼠模型中，大脑中tau蛋白的降低减少了网络功能障碍（一项研究）。 AD的早期迹象）和认知能力下降。使用反义寡核苷酸使大脑tau水平延长降低达75% 寡核苷酸在啮齿动物和非人灵长类动物中不引起明显的不良事件。因此，tau减少 应该不会有太大的副作用由于不同形式的tau蛋白可能有助于神经发病机制，我们 旨在用小分子药物降低总体tau水平，以在不同的tau蛋白病中获得最广泛的益处。到 为了发现降低神经元tau水平的小分子，我们使用高通量筛选来评估 20，000种结构不同的化合物在脑神经元中的功效。其中一种化合物GL 05520， 在啮齿类动物和人类神经元中以剂量依赖性方式的tau蛋白水平和降低的神经元MAPT mRNA水平高达75%，而不影响编码淀粉样前体蛋白或管家的转录本 proteins. GL 05520的初步构效关系（SAR）研究鉴定了三种类似物， 提供改善母体化合物的生理化学和药理学性质的机会。 来自我们初步筛选的另一种化合物GL 05522也降低了神经元tau蛋白水平，但没有 影响Mapt mRNA水平，表明不同的作用机制。GL 05522是一种潜在的备份 如果不可预见的责任限制了GL 05520类似物的开发，则可以使用化合物。基于药物样结构 在我们鉴定的tau还原剂中，我们提出了一个药物化学计划来提高它们的效力， 药理学特性将在目标去卷积研究中评价优化的化合物，以确定 他们最有可能的作用机制，这将有助于进一步改善额外的一轮药物治疗。 化学物质直接作用于目标。将在标准药代动力学中测试优化的化合物 体内稳定性和脑生物利用度的研究。最有希望的化合物将在安全性方面进行评估 问题研究疗效研究将测试先导化合物降低脑内非纤维性和纤维性神经递质水平的能力。 在啮齿动物模型中的tau蛋白。这些研究可以为开发更有效的治疗方法铺平道路， 可以改变AD和相关疾病的治疗。

PROJECT SUMMARY Our goal is to identify or generate small molecules that safely and effectively lower brain levels of the microtubule- associated protein tau (MAPT) and could be developed into drugs to treat Alzheimer’s disease (AD) and other tauopathies in which tau contributes to neurodegeneration and cognitive decline. Since tau also enables pathogenic effects of other AD-related proteins (e.g., Aβ and apoE4), reducing tau levels could lessen the effects of multiple drivers of this multifactorial condition and provide a more effective treatment than other monotherapies that have failed in clinical trials. In mouse models, tau lowering in the brain reduces network dysfunction (an early sign of AD) and cognitive decline. Prolonged reduction of cerebral tau levels by up to 75% with antisense oligonucleotides does not elicit overt adverse events in rodents and nonhuman primates. Thus, tau reduction should have limited on-target side effects. Since different forms of tau may contribute to neuropathogenesis, we aim to reduce overall tau levels with small-molecule drugs for the broadest benefit in diverse tauopathies. To discover small molecules that reduce neuronal tau levels, we used high-throughput screening to assess the efficacy of 20,000 structurally diverse compounds in brain neurons. One of these compounds, GL05520, reduced tau protein levels in a dose-dependent manner in rodent and human neurons and reduced neuronal MAPT mRNA levels by up to 75% without affecting transcripts encoding amyloid precursor protein or housekeeping proteins. Preliminary structure-activity relationship (SAR) studies of GL05520 identified three analogs that provide opportunities to improve the physiochemical and pharmacologic properties of the parent compound. Another compound from our primary screen, GL05522, also reduced neuronal tau protein levels but without affecting Mapt mRNA levels, suggesting a different mechanism of action. GL05522 is a potential backup compound if unforeseen liabilities limit the development of GL05520 analogs. Based on the drug-like structures of the tau reducers we identified, we propose a medicinal chemistry plan to improve their potency and pharmacological properties. Optimized compounds will be evaluated in target deconvolution studies to identify their likeliest mechanisms of action, which will facilitate further improvement by an additional round of medicinal chemistry directed at the identified target. Optimized compounds will be tested in standard pharmacokinetic studies of in vivo stability and brain bioavailability. The most promising compounds will be assessed in safety studies. Efficacy studies will test the ability of the lead compounds to reduce brain levels of nonfibrillar and fibrillar tau in rodent models. These studies could pave the way to the development of more effective therapeutics that could transform the treatment of AD and related conditions.