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

项目摘要 Avanti Biosciences的使命是开发有效的阿尔茨海默病（AD）治疗方法。 最近的科学发现已经确定过度磷酸化的tau蛋白是疾病的有毒罪魁祸首 进展导致形成神经纤维缠结（NFT），这是神经纤维缠结的主要标志之一。 疾病。已证明激酶DYRK 1A在肿瘤发生中具有直接作用。 tau的磷酸化。DYRK1A免疫反应性增加已在 内嗅皮层、海马和新皮层散在神经元胞质和胞核 与tau蛋白磷酸化相关的神经退行性疾病，包括阿尔茨海默氏症， 疾病DYRK1A诱导的tau蛋白磷酸化降低tau蛋白的生物学活性 并促进tau的自聚集和纤维化。异常的tau蛋白磷酸化导致 tau蛋白生物学功能的丧失，导致刺激微管的活性降低 组装件.神经元变性是神经元死亡和痴呆的主要原因， AD和AD。DYRK1A参与神经退行性变表明， DYRK1A活性的治疗性抑制被假设为疾病改善治疗 这将在整个疾病过程中有效，并对患者的生活产生重大影响。 数以百万计的老年痴呆症患者。 目前，专门针对DYRK1A调节的制药工业努力正在进行中。 有限公司Avanti Biosciences是唯一专注于发现小分子生物学的公司之一。 分子DYRK1A调节剂来自天然儿茶素。据报道，主要 绿色茶成分表没食子儿茶素没食子酸酯（EGCG）是一种有效的变构抑制剂， DYRK1A。在努力发现新的衍生物，发挥相同的活性和改善 类药性我们对绿色茶的各种成分进行了筛选。我们的惊喜， EGCG不是混合物中最有效的儿茶素。反式儿茶素衍生物 没食子儿茶素没食子酸酯（GCG）和儿茶素没食子酸酯（GC）显示出改善的活性， 增加化学稳定性。在赠款的第一阶段，我们发现CG 与EGCG相比， 我们现在能够以治疗浓度到达大脑。我们还能够 为了证明我们的先导化合物可以明确地在两种酶的作用下与靶标结合， 和细胞水平，并减少tau蛋白的磷酸化， 与AD进展有关。该项目现在准备进入第二阶段，我们将 在动物模型中进一步评估我们的先导化合物， 问题研究Avanti Biosciences正在申请行政补助，以满足增加的成本 在批准的裁决范围内，但在申请时没有预见到的 已提交。本补充侧重于鼻内制剂的开发， 在我们的有效性和安全性动物研究的第二阶段资助期间使用。

PROJECT SUMMARY Avanti Biosciences’ mission is to develop effective therapeutics for Alzheimer’s disease (AD). Recent scientific discoveries have identified hyperphosphorylated tau as toxic culprits in disease progression leading to the formation of neurofibrillary tangles (NFTs), one of the main hallmark of the disease. The kinase DYRK1A has been shown to have a direct role in the phosphorylation of tau. Increased DYRK1A immunoreactivity has been reported in the cytoplasm and nuclei of scattered neurons of the entorhinal cortex, hippocampus and neocortex in neurodegenerative diseases associated with tau phosphorylation, including Alzheimer’s disease. DYRK1A induced phosphorylation of tau reduces the biological activity of tau protein and promotes tau self-aggregation and fibrillization. The abnormal tau phosphorylation causes the loss of tau biological function, resulting in reduced activity to stimulate microtubule assembly. Neurofibrillary degeneration is the leading cause of neuronal death and dementia in DS⁄AD and AD. The involvement of DYRK1A in neurofibrillary degeneration indicates that therapeutic inhibition of DYRK1A activity are hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of the millions of Alzheimer’s patients. Pharmaceutical industry efforts targeted specifically at modulation of DYRK1A are currently limited. Avanti Biosciences is one of the only companies uniquely focused on discovery of small molecule DYRK1A modulator derived from natural catechins. It has been reported that the main ingredient of green tea, epigallocatechin gallate (EGCG) is a potent allosteric inhibitor of DYRK1A. In an effort to discover new derivatives that exert the same activity and improved drug-like properties we have screened the various component of green tea. With our surprise, EGCG was not the most potent catechin in the mixture. The trans catechin derivatives Gallocatechin gallate (GCG) and Catechin gallate (GC) showed improved activity combined with an increased chemical stability. During the first phase of the grant we have discovered that CG has much improved ADME properties compared to EGCG and using our proprietary intranasal formulation we are now able to reach the brain in therapeutic concentrations. We were also able to demonstrate that our lead compound unequivocally can engage the target at both enzymatic and cellular levels and to reduce the phosphorylation of tau which has been shown to be relevant in the AD progression. The project is now ready to enter into Phase 2 were we will further evaluate our lead compound in the animal model and looking in more detail at safety studies. Avanti Biosciences is requesting an administrative supplement to meet increased costs that are within the scope of the approved award but were unforeseen when the application was submitted. This supplement focuses on the development of an intranasal formulation to be used during Phase 2 of the grant in our efficacy and safety animal studies.