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， 没有可用的治疗疾病的方法。大多数治疗方法只攻击一种疾病成分， 例如，β-淀粉样蛋白或tau蛋白通路。然而，多效性干预很可能是 需要的。双特异性酪氨酸磷酸化调节激酶1A(Dyrk1a)蛋白代表一种 这样的靶点，在β-淀粉样蛋白、tau和神经炎性通路中具有活性。这些路径中的每一个 导致阿尔茨海默病的神经退化和认知缺陷。因此，抑制Dyrk1a的化合物提供了一种 通过同时调节tau、淀粉样蛋白和 神经炎性通路。为此，我们的药物化学努力提供了一个强大的和大脑 渗透剂分子Dyr219在3xTg-AD模型中给药后，可以改善行为和tau和 无明显不良反应的AD的淀粉样神经病理特征(Branca等人，Aging Cell，2017，16(5)， 1146-1154)。在最近一项为期6个月的研究中，我们没有观察到野生型或3xTg-AD小鼠的运动效应 在慢性每日给药后，不溶性、过度磷酸化的tau、神经原纤维的较大减少 缠结和不溶性A？42多肽和淀粉样斑块。最近，我们已经证实Dyr219还可以触发Dyrk1a蛋白的降解，这归因于抑制Dyrk1a自动磷酸化过程。这一效应降低了体内活性Dyrk1A的水平，有助于提高疗效，并表明Dyr219脑暴露与强大的神经病理效应之间存在PK-PD关系。正在进行的旨在提高口服生物利用度和动态组选择性的药物化学努力最近提供了显著改善的类似物(Dyr476：F%73%，B/P 0.39)和(DYR533：F%100%，B/P 0.30 S(35)-选择性分数0.03)。重要的是，Samumed最近宣布发现了SM07883，一种Ind就绪的、有效的口服1型Dyrk1a抑制剂，表现出显著的tau病理 对JNPL3小鼠的抑制作用。我们认为后者验证了我们的短期临床前假设的可行性，并且 支持本文所述目标的必要性。综上所述，我们提出了一个强大的药物化学管道，再加上在小鼠身上进行的有希望的化合物的体内测试，目的是提供比Dyr219更好的分子，解决口服生物利用度，在临床前毒理学模型中被认为是安全的，并概括其体内效应。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.