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DYRK1A Inhibition as a Novel Treatment Approach for Alzheimer's Disease

DYRK1A 抑制作为阿尔茨海默病的新治疗方法

基本信息

批准号：
9886310
负责人：
TRAVIS L DUNCKLEY
金额：
$ 77.88万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9886310
关键词：
3xTg-AD mouse Address Adverse effects Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Back Behavioral Binding Bioavailable Biological Assay Biological Availability Brain Cell Aging Chronic Cognition Cognition Disorders Cognitive Cognitive deficits Coupled Crystallization Data Development Disease Dose Exhibits Goals Hand Impaired cognition In Vitro Intervention Life Measures Medical Modeling Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Oral Pathology Pathway interactions Peptides Pharmaceutical Chemistry Phosphorylation Phosphotransferases Process Proteins Role Selection Criteria Senile Plaques Specificity Structure Testing Therapeutic Time Triage Tyrosine Phosphorylation abeta accumulation amyloid pathology analog attenuation base clinical toxicology cognitive enhancement design hyperphosphorylated tau improved in vivo in vivo evaluation inhibitor/antagonist mouse model neuroinflammation neuropathology novel novel therapeutic intervention pre-clinical protein degradation screening small molecule success tau Proteins tau aggregation

项目摘要

Alzheimer's disease (AD) is an increasingly common and devastating neurodegenerative disease with no available disease-modifying treatments. Most treatment approaches attack a single disease component, either the β-amyloid or tau protein pathways, for example. However, pleiotropic interventions will likely be needed. The dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) protein represents one such target, with activity in β-amyloid, tau, and neuroinflammatory pathways. Each of these pathways contributes to neurodegeneration and cognitive deficits in AD. As such, compounds that inhibit Dyrk1a offer a promising new therapeutic approach through novel simultaneous modulation of tau, amyloid, and neuroinflammatory pathways. To this end, our medicinal chemistry efforts have delivered a potent and brain penetrant molecule, Dyr219, which upon dosing in the 3xTg-AD model, improves behavioral and both tau and amyloid neuropathological features of AD with no overt adverse effects (Branca et al., Aging Cell, 2017, 16(5), 1146-1154). In a recent extended 6-month study, we observe no motor effects in wild-type or 3xTg-AD mice following chronic daily dosing, and larger reductions to insoluble, hyperphosphorylated tau, neurofibrillary tangles and insoluble Aß42 peptides and amyloid plaques. Recently, we have confirmed that Dyr219 also triggers Dyrk1a protein degradation, assigned to inhibition of the Dyrk1a autophosphorylation process. This effect reduces levels of active Dyrk1A in vivo, contributing to efficacy and pointing to a PK-PD relationship between Dyr219 brain exposure and robust neuropathological effects. Ongoing medicinal chemistry efforts directed at enhancement of oral bioavailability and kinome selectivity have recently delivered significantly improved analogs (Dyr476: F% 73%, B/P 0.39) and (DYR533: F% 100%, B/P 0.30 S(35)-selectivity score 0.03). Importantly, Samumed has recently announced the discovery of SM07883, an IND-ready, potent, oral Type 1 Dyrk1a inhibitor which exhibits significant tau pathology reduction in JNPL3 mice. We feel the latter validates the feasibility of our short-term pre-clinical hypothesis and supports the necessity of the aims described herein. In summary, we propose a robust medicinal chemistry pipeline, coupled with in vivo testing of promising compounds in mice, with the aim of delivering molecules superior to Dyr219 that address oral bioavailability, are deemed safe in pre-clinical toxicology models and recapitulate its in vivo effects. We expect our new molecules to be effective at modifying the course of pathology and cognitive decline in AD.

阿尔茨海默病 (AD) 是一种日益常见且具有破坏性的神经退行性疾病，没有可用的疾病缓解治疗方法。大多数治疗方法针对单一疾病成分，例如，β-淀粉样蛋白或 tau 蛋白途径。然而，多效性干预措施可能会需要。双特异性酪氨酸磷酸化调节激酶 1A (Dyrk1a) 蛋白代表一种这样的目标，在 β-淀粉样蛋白、tau 蛋白和神经炎症途径中具有活性。这些途径中的每一个导致 AD 中的神经退行性变和认知缺陷。因此，抑制 Dyrk1a 的化合物提供了通过新颖的同时调节 tau、淀粉样蛋白和神经炎症途径。为此，我们的药物化学努力提供了有效的大脑渗透分子 Dyr219 在 3xTg-AD 模型中给药后，可改善行为以及 tau 和 AD 的淀粉样蛋白神经病理学特征，没有明显的副作用（Branca 等人，Aging Cell, 2017, 16(5), 1146-1154）。在最近一项为期 6 个月的长期研究中，我们观察到野生型或 3xTg-AD 小鼠没有运动效应长期每日给药后，不溶性、过度磷酸化的 tau 蛋白、神经原纤维大量减少缠结和不溶性 Aß42 肽以及淀粉样斑块。最近，我们证实 Dyr219 也会触发 Dyrk1a 蛋白降解，从而抑制 Dyrk1a 自磷酸化过程。这种效应降低了体内活性 Dyrk1A 的水平，有助于提高功效，并指出 Dyr219 大脑暴露与强大的神经病理学效应之间的 PK-PD 关系。正在进行的旨在提高口服生物利用度和激酶组选择性的药物化学努力最近已显着改善了类似物（Dyr476：F% 73%，B/P 0.39）和（DYR533：F% 100%，B/P 0.30 S(35)-选择性评分 0.03）。重要的是，Samumed 最近宣布发现了 SM07883，这是一种可用于 IND 的强效口服 1 型 Dyrk1a 抑制剂，具有显着的 tau 病理学特征 JNPL3 小鼠的减少。我们认为后者验证了我们短期临床前假设的可行性支持本文所述目标的必要性。总之，我们提出了一个强大的药物化学管道，再加上对小鼠体内有前景的化合物进行体内测试，目的是提供优于 Dyr219 的分子，解决口服生物利用度问题，在临床前毒理学模型中被认为是安全的，并重现其体内效应。我们期望我们的新分子能够有效改变 AD 的病理过程和认知能力下降。