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：
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
项目类别：
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&apos s Disease Alzheimer&apos 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

Abeta synthesis Affect Affinity Alzheimer&apos s Disease Alzheimer&apos 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

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项目摘要

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.

项目摘要该提案旨在开发ABI-171，这是“双特异性酪氨酸”的潜在和选择性抑制剂（y） - 磷酸化调节激酶-1a”（DYRK1A），以治疗轻度至中度的阿尔茨海默氏病（AD）由于其在关键靶蛋白（如淀粉样蛋白前体蛋白）的炎症和磷酸化中的作用（APP），Presenilin-1（PS1）和Tau。 AD是一种神经退行性障碍，其特征是神经退行性死亡和灰质的丧失额叶皮层和海马。记忆丧失是AD的典型症状，已与淀粉样蛋白斑块和神经原纤维缠结（NFTS）的积累。引人入胜的数据指向热磷酸化的tau物种是AD中毒性的介体；他们参与形成NFT的存在与疾病进展紧密相关。根据β-淀粉样cascade假设的说法不溶性β-淀粉样蛋白的沉积负责神经元死亡。斑块由β-淀粉样蛋白构成通过通过β-和γ-分泌酶裂解淀粉样蛋白前体蛋白（APP）产生的肽（Aβ）。 DYRK1A是一种指导的丝氨酸/苏氨酸激酶，许多蛋白显示为底物1。 DYRK1A活性可能与AD发病机理有关，因为（1）它在中枢神经系统神经元中持有强劲表达；（2）通过靶向NRF2和GFAP直接衰减注射；（3）dyrk1a直接磷酸化应用程序，然后将APP的泌尿酶介导的裂解增加到Aβ肽中。（4）dyrk1a是一种激酶用作底物，其存在与tau的磷酸化增加有关。（5）dyrk1a选择性抑制剂ABI-171在Pilot 5XFAD有效模型（AD动物模型）中有效。值得注意的是，dyrk1a Primes tau可通过GSK3β激酶进行额外的磷酸化，这是有助于AD发病机理的。（6）dyrk1a磷酸化pS1γ-分泌酶的亚基，而这种磷酸化事件增加了γ-分泌酶蛋白酶活性，进一步升高Aβ肽的产生。这些发现支持我们抑制的假设 DYRK1A活性将是疾病改良的，并显着影响AD患者的生活。尽管DYRK1A在AD发病机理中发挥了作用，但很少有药物行业的努力针对调节该酶。 Avanti Biosciences特别专注于发现负调节剂大脑中的dyrk1a的选择性。这种商业化准备飞行员（CRP）赠款将使我们能够继续原始赠款1R44AG056181的工作使我们能够确认药物在治疗中的效率 AD，更详细地研究其作用机理，完成CMC和安全研究是必要的向IND提交FDA。在这笔赠款中，提出了四个具体目标（SA）：在SA1中，我们建议研究慢性分子探索了作用机理的AD模型。在SA2中，我们研究了药物的毒性和确定其治疗指数。在SA 3中，我们进行了化学，制造和控制（CMC）活动辅助药理学/毒理学测试。最后，在SA4中，我们进行了IND促进研究，包括毒理学，安全性和遗传毒性研究。该建议将生成提交IND所需的所有信息，并将项目移至临床试验阶段。