Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease

项目摘要 该提案旨在开发ABI-171，这是一种有效的选择性“双特异性酪氨酸激酶”抑制剂。 （Y）-磷酸化调节激酶-1A”（DYRK 1A），用于治疗轻度至中度阿尔茨海默病（AD） 因为它在炎症和关键靶蛋白如淀粉样前体蛋白的磷酸化中起作用 (APP)、早老素-1（PS1）和tau. AD是一种神经退行性疾病，其特征在于神经元死亡和大脑中灰质的损失。 额叶皮层和海马体记忆力丧失是AD的典型症状， 淀粉样斑块和神经纤维缠结（NFT）的积累。大量令人信服的数据表明， 过度磷酸化的tau物质作为AD毒性的介导剂;它们参与形成NFT， 存在与疾病进展密切相关。根据β-淀粉样蛋白级联假说， 不溶性β-淀粉样蛋白的沉积是神经元死亡的原因。斑块由β-淀粉样蛋白构成 通过β-和γ-分泌酶切割淀粉样前体蛋白（APP）产生的肽（Aβ）。 DYRK 1A是一种脯氨酸导向的丝氨酸/苏氨酸激酶，许多蛋白质被显示为底物1。 DYRK 1A活性可能参与AD发病机制，因为（1）它在CNS神经元中稳健表达;（2） 通过靶向Nrf 2和GFAP直接减弱炎症;（3）DYRK 1A直接磷酸化APP， 增加分泌酶介导的APP裂解为Aβ肽;（4）DYRK 1A是一种激酶，tau蛋白 作为底物，其存在与tau的磷酸化增加有关;（5）DYRK 1A选择性 抑制剂ABI-171在试验性5xFAD功效模型（AD动物模型）中是有效的。DYRK1A 引发tau通过GSK 3 β激酶的额外磷酸化，这已知有助于AD发病机制。 (6)DYRK 1A磷酸化γ-分泌酶的PS1 a亚基，这种磷酸化事件增加γ-分泌酶 蛋白酶活性，进一步提高Aβ肽产量。这些发现支持了我们的假设， DYRK 1A活性的增加将改变疾病，并显著影响AD患者的生活。 尽管DYRK 1A在AD发病机制中发挥作用，但制药行业很少有针对该调节的努力 这种酶。Avanti Biosciences特别专注于发现负调节剂 DYRK 1A在大脑中的作用这项商业化准备试点（CRP）赠款将使我们能够继续 原始授权1 R44 AG 056181的工作，使我们能够确认药物在治疗中的疗效 更详细地研究其作用机制，完成必要的CMC和安全性研究， 向FDA提交IND申请 在这项资助中，提出了四个具体目标（SA）：在SA 1中，我们提出在慢性炎症中研究该分子。 AD模型，其中探索了作用机制。在SA 2中，我们研究了药物的毒性， 确定其治疗指数。在SA 3中，我们有化学、制造和控制（CMC）活动， IND使能药理学/毒理学试验。最后，在SA 4中，我们有IND使能研究，包括 毒理学、安全性和遗传毒性研究。 该提案将生成提交IND所需的所有信息，并将项目转移到临床 审判阶段

PROJECT SUMMARY This proposal aims to develop ABI-171, a potent and selective inhibitor of the “Dual-specificity tyrosine- (Y)-phosphorylation Regulated Kinase-1A” (DYRK1A), to treat mild to moderate Alzheimer’s disease (AD) because of its role in inflammation and phosphorylation of key target protein like Amyloid Precursor Protein (APP), Presenilin-1 (PS1), and tau. AD is a neurodegenerative disorder is characterized by neuronal death and loss of gray matter in the frontal cortex and hippocampus. Memory loss is a typical symptom of AD and has been linked to the accumulation of amyloid plaques and neurofibrillary tangles (NFTs). A compelling body of data points to hyperphosphorylated tau species as mediators of toxicity in AD; they participate in forming NFTs whose presence is closely linked with disease progression. According to the β-amyloid cascade hypothesis, the deposition of insoluble β-amyloid is responsible for neuronal death. Plaques are constituted by β-amyloid peptides (Aβ) that are generated via the cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. DYRK1A is a proline-directed serine/threonine kinase for which many proteins are shown as substrate1. DYRK1A activity may be involved in AD pathogenesis because (1) it is robustly expressed in CNS neurons; (2) directly attenuate inflammation by targeting Nrf2 and GFAP; (3) DYRK1A phosphorylates APP directly and increases the secretase-mediated cleavage of APP into Aβ peptides; (4) DYRK1A is a kinase for which tau serves as a substrate and its presence is associated with increased phosphorylation of tau; (5) DYRK1A selective inhibitor ABI-171 is efficacious in a pilot 5xFAD efficacy model, an AD animal model. Significantly, DYRK1A primes tau for additional phosphorylation by GSK3β kinase, which is known to contribute to AD pathogenesis. (6) DYRK1A phosphorylates PS1 a subunit of γ-secretase, and this phosphorylation event increases γ-secretase protease activity, further elevating Aβ peptide production. These findings support our hypothesis that inhibition of DYRK1A activity will be disease-modifying and significantly impact the lives of those with AD. Despite a role for DYRK1A in AD pathogenesis, few pharmaceutical industry efforts target the modulation of this enzyme. Avanti Biosciences is specifically and uniquely focused on discovering negative modulators selectively of DYRK1A in the brain. This Commercialization Readiness Pilot (CRP) grant will allow us to continue the work from the original grant 1R44AG056181 and enable us to confirm the efficacy of the drug in the treatment of AD, study in more detail its mechanism of action, complete the CMC and safety studies that are necessary to file an IND with the FDA. In this grant, four specific aims (SA) are proposed: in SA1 we propose studying the molecule in a chronic model of AD in which the mechanism of action is explored. In SA2 we investigate the toxicity of the drug and determine its therapeutic index. In SA 3 we have the Chemistry, Manufacturing, and Control (CMC) activities for IND-enabling pharmacology/toxicology tests. Finally, in SA4 we have the IND enabling studies, including toxicology, safety, and genotoxicity studies. This proposal will generate all the information needed for filing an IND and move the project to the clinical trial stage.