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

开发用于治疗阿尔茨海默病的 DYRK1A 变构调节剂

基本信息

批准号：
9932627
负责人：
Gian Luca Araldi
金额：
$ 35万
依托单位：
AVANTI BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9932627
关键词：
Administrative Supplement Alzheimer&apos s Disease Animal Model Award Basic Science Biological Biological Process Biological Sciences Brain Catechin Cell Nucleus Collaborations Cytoplasm Dementia Development Disease Disease Progression Drug Industry Epigallocatechin Gallate Formulation Functional disorder Grant Green tea Hippocampus (Brain)Institutes Lead Link Mediating Microtubules Mission Neocortex Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Pathogenesis Patients Pharmaceutical Preparations Phase Phosphotransferases Property Reporting Role Synapses Therapeutic Treatment Efficacy animal safety chemical stability cost entorhinal cortex gallocatechol hyperphosphorylated tau immunoreactivity improved inhibitor/antagonist neurofibrillary tangle formation neuron loss safety study small molecule tau Proteins tau mutation tau phosphorylation tau-1

项目摘要

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.

项目摘要 Avanti Biosciences的使命是为阿尔茨海默氏病（AD）开发有效的治疗疗法。最近的科学发现已将过度磷酸化的tau视为疾病的有毒罪犯导致神经原纤维缠结（NFTS）形成的进展，这是主要标志之一疾病。激酶dyRK1a已显示在 tau的磷酸化。在内嗅皮层，海马和新皮层的散射神经元的细胞质和核在与tau磷酸化相关的神经退行性疾病中，包括阿尔茨海默氏症疾病。 dyRK1a诱导的tau磷酸化降低了tau蛋白的生物学活性并促进tau自我聚集和纤维化。异常TAU磷酸化原因 Tau生物学功能的丧失，导致活性降低以刺激微管集会。神经原纤维变性是神经元死亡和痴呆症的主要原因 DS⁄AD和AD。 Dyrk1a参与神经原纤维变性表明假设对DYRK1A活性的治疗性抑制作用是疾病改良治疗这将在整个疾病的整个过程中有效，并显着影响数百万阿尔茨海默氏症患者。目前专门针对DYRK1A调制的药物行业努力有限的。 Avanti Biosciences是唯一专注于发现小的公司之一分子dyrk1a调节剂来自天然儿茶素。据报道，主要绿茶的成分，上瓜酸酯食酸酯（EGCG）是潜在的变构抑制剂 dyrk1a。为了发现发挥相同活动并改善的新衍生物我们已经筛选了绿茶的各个成分。令人惊讶的是 EGCG不是混合物中最有效的儿茶素。反式儿茶素衍生物 Gallocatechin Gallate（GCG）和Catechin Gallate（GC）显示了改善的活动化学稳定性提高。在赠款的第一阶段，我们发现CG 与EGCG相比，ADME特性得到了很大改善，并使用我们的专有鼻内形成我们现在能够以治疗浓度到达大脑。我们也能为了证明我们的铅化合物可以明确地参与两个酶促的目标和细胞水平，并降低Tau的磷酸化，这已被证明为与广告进展相关。如果我们愿意，该项目现在准备进入第二阶段进一步评估我们的动物模型中的铅化合物，并更详细地研究安全研究。 Avanti Biosciences要求提供行政补品以满足增加的成本在批准裁决的范围内，但在申请时就无法预料提交。这种补充的重点是开发鼻内公式在我们的效率和安全动物研究中，在赠款的第2阶段使用。