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

• 批准号: 10708925
• 负责人: Gian Luca Araldi
• 金额: $ 123.93万
• 依托单位: AVANTI BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708925
• 关键词: Abeta synthesis; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Disease Models; Animals; Anti-Inflammatory Agents; Astrocytosis; Attenuated; Basic Science; Biological Availability; Biological Sciences; Brain; Canis familiaris; Cardiovascular system; Catechin; Chemistry; Chronic; Clinic; Clinical Trials; Cognition; Collaborations; Corpus striatum structure; Data; Deposition; Development; Devices; Disease; Disease Progression; Dose; Drug Industry; Drug toxicity; Enzymes; Event; Family; Formulation; Funding; Glial Fibrillary Acidic Protein; Gliosis; Grant; Hepatocyte; Hepatotoxicity; Hippocampus; Human; IL17 gene; In Vitro; Inflammation; Interferon Type II; Interleukin-1 beta; Interleukin-6; Investigational New Drug Application; Lead; Link; Measures; Mediating; Mediator; Memory Loss; Metabolism; Methods; Modeling; Monkeys; Mus; NQO1 gene; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Nose; Oxidases; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phosphorylation; Phosphotransferases; Plasma; Production; Proline; Property; Protein-Serine-Threonine Kinases; Proteins; Quinones; Rattus; Rodent; Role; STAT3 gene; Safety; Senile Plaques; Series; Serine; Specificity; Symptoms; Synapses; TNF gene; Testing; Therapeutic Index; Tissues; Toxic effect; Toxicology; Tyrosine; Vascular Endothelial Growth Factors; Western Blotting; Work; behavior test; beta secretase; beta-site APP cleaving enzyme 1; commercialization readiness; density; drug efficacy; efficacy study; frontal lobe; gamma secretase; genotoxicity; glycogen synthase kinase 3 beta; good laboratory practice; gray matter; hyperphosphorylated tau; in vivo; inhibitor; interest; lead optimization; manufacture; medication safety; member; morris water maze; nephrotoxicity; neurofibrillary tangle formation; neuroinflammation; neuron loss; novel therapeutics; nuclear factors of activated T-cells; pharmacokinetics and pharmacodynamics; pharmacologic; preclinical development; preclinical study; presenilin-1; prevent; proto-oncogene protein pim-1; respiratory; safety study; safety testing; secretase; side effect; tau Proteins; tau aggregation; tau-1

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.

项目总结 这项建议旨在开发ABI-171，一种有效的和选择性的“双特异性酪氨酸- (Y)-磷酸化调节激酶-1A“(DYRK1A)，用于治疗轻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是一种以神经元死亡和灰质丢失为特征的神经退行性疾病 额叶皮质和海马体。记忆丧失是阿尔茨海默病的典型症状，与 淀粉样斑块和神经原纤维缠结(NFT)的堆积。令人信服的数据指向 过度磷酸化的tau物种作为AD毒性的媒介；它们参与形成NFTs，其 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-淀粉样蛋白组成 多肽(Aβ)是通过β-和γ-分泌酶裂解淀粉样前体蛋白(APP)而产生的。 DYRK1a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。 DYRK1A活性可能参与AD的发病机制：(1)DYRK1A在中枢神经系统神经元中强势表达；(2) 通过靶向Nrf2和GFAP直接抗炎；(3)DYRK1A直接磷酸化APP并 增加分泌酶介导的APP裂解为Aβ多肽；(4)DYRK1a是一种与tau 作为底物，它的存在与tau的磷酸化增加有关；(5)DYRK1A选择性 抑制剂ABI-171在实验性的5xFAD疗效模型，即AD动物模型中是有效的。值得注意的是，DYRK1A 启动tau的额外磷酸化的Gsk3β激酶，这是已知有助于AD的发病。 (6)DYRK1a使γ分泌酶的一个亚单位pS1磷酸化，使γ分泌酶的活性增加 蛋白水解酶活性，进一步提高Aβ多肽产量。这些发现支持我们的假设，即抑制 DYRK1A活性的增加将改善疾病，并显著影响阿尔茨海默病患者的生活。 尽管DYRK1A在AD发病机制中发挥了作用，但制药行业很少有针对这种调节的努力 这种酶的活性。Avanti生物科学公司专门和独特地专注于发现负调节因子 DYRK1a在大脑中的选择性。这项商业化准备试验(CRP)拨款将使我们能够继续 该工作来源于原授予的1R44AG056181，并使我们能够确认该药物在治疗中的疗效 AD，更详细地研究其作用机制，完成CMC和安全性研究，这是必要的 向FDA提交IND。 在这项拨款中，提出了四个特定的目标(SA)：在SA1中，我们建议研究慢性粒细胞白血病的分子。 探讨其作用机制的AD模型。在SA2中，我们调查了药物的毒性和 测定其治疗指数。在SA 3中，我们有化学、制造和控制(CMC)活动 IND-Enabling药理学/毒理学测试。最后，在SA4中，我们有支持IND的研究，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，并将该项目转移到临床 审判阶段。