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

阿尔茨海默病（AD）是一种日益常见和破坏性的神经退行性疾病， 没有可用的疾病改善治疗。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，多效性干预可能会 needed.双特异性酪氨酸磷酸化调节激酶1A（Dyrk 1a）蛋白代表了一种 这些靶点在β-淀粉样蛋白、tau和神经炎症途径中具有活性。每一种途径 导致AD中的神经变性和认知缺陷。因此，抑制Dyrk 1a的化合物提供了 通过新的同时调节tau蛋白、淀粉样蛋白和 神经炎症通路。为此，我们的药物化学努力已经提供了一个强大的和大脑 渗透剂分子Dyr 219，其在3xTg-AD模型中给药后，改善行为和tau和 没有明显副作用的AD的淀粉样蛋白神经病理学特征（Branca等，衰老细胞，2017，16（5）， 1146-1154）。在最近一项为期6个月的延长研究中，我们观察到野生型或3xTg-AD小鼠没有运动效应。 在长期每日给药后，不溶性、过度磷酸化的tau蛋白大量减少， 缠结和不溶性A β 42肽和淀粉样斑块。最近，我们已经证实，Dyr 219也触发Dyrk 1a蛋白降解，分配到抑制Dyrk 1a自磷酸化过程。这种效应降低了体内活性Dyrk 1A的水平，有助于疗效，并指出Dyr 219脑暴露与强大的神经病理学效应之间的PK-PD关系。针对增强口服生物利用度和激酶组选择性的正在进行的药物化学努力最近已经提供了显著改善的类似物（Dyr 476：F% 73%，B/P 0.39）和（DYR 533：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SM 07883，这是一种IND就绪的强效口服1型Dyrk 1a抑制剂，表现出显著的tau病理学 JNPL 3小鼠中的减少。我们认为后者验证了我们的短期临床前假设的可行性， 支持本文所述目的的必要性。总之，我们提出了一个强大的药物化学管道，加上在小鼠体内测试有前途的化合物，目的是提供分子上级的Dyr 219，解决口服生物利用度，被认为是安全的临床前毒理学模型和概括其体内作用。我们希望我们的新分子能有效地改变AD的病理过程和认知能力下降。

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.