Small Molecule Mitochondria-Targeted Therapeutics for AD

小分子线粒体靶向治疗 AD

• 批准号: 10576450
• 负责人: Eugenia Trushina
• 金额: $ 77.84万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576450
• 关键词: APP-PS1; Abeta synthesis; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Binding; Biochemical; Biochemistry; Biogenesis; Biological Assay; Biological Availability; Biological Markers; Blinded; Blood; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Caloric Restriction; Cell Differentiation process; Chemicals; Chemistry; Chronology; Clinic; Clinical; Clinical Investigator; Clinical Trials; Cognitive; Competitive Binding; Complex; Computational Biology; Data; Data Discovery; Dendritic Spines; Development; Disease; Disease Progression; Documentation; Dose; Ensure; Evaluation; Exercise; Exhibits; Fibroblasts; Flavin Mononucleotide; Formulation; Freedom; Functional disorder; Goals; Grant; High Fat Diet; Homeostasis; Human; In Vitro; Individual; Inflammation; Infrastructure; Investigation; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Legal patent; Long-Term Potentiation; Lymphocyte; Measures; Meta-Analysis; Methodology; Mitochondria; Molecular; Molecular Target; Mus; Nerve Degeneration; Neurons; Oral; Outcome; Oxidation-Reduction; Oxidative Stress; Pamphlets; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase I Clinical Trials; Play; Positron-Emission Tomography; Preparation; Prevention; Probability; Process; Production; Property; Protein Kinase; Proteins; Reporting; Research; Research Personnel; Resistance; Resources; Risk; Safety; Series; Signal Transduction; Specificity; Stream; Structure-Activity Relationship; Synapses; System; Systems Biology; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Translations; Validation; Variant; Wild Type Mouse; Work; Writing; aged; base; cognitive function; drug candidate; effective therapy; efficacy study; familial Alzheimer disease; fluorodeoxyglucose; glucose uptake; glycogen synthase kinase 3 beta; improved; in vivo; in vivo evaluation; induced pluripotent stem cell; inhibitor; lead optimization; lead series; mouse model; neuroprotection; next generation; novel; novel strategies; pre-clinical; preclinical development; preclinical study; prevent; response; scale up; screening; small molecule; small molecule therapeutics; success; targeted biomarker; targeted treatment; transcriptome sequencing; translational potential; translational study; translational therapeutics

Abstract Abnormal energy homeostasis in Alzheimer’s Disease (AD) is associated with synaptic dysfunction and neurodegeneration. Emerging data generated using multiple systems biology approaches and meta-analysis in AD patients identified an AMP-protein kinase (AMPK) integrated signaling network that operates down stream of mitochondrial energy production and could provide neuroprotection in AD. We show that partial inhibition of mitochondrial complex I (MCI) improves glucose uptake and utilization, dendritic spine maturation, long-term potentiation, synaptic activity, cognitive function, and reduces Aβ and pTau accumulation, oxidative stress and inflammation resulting in neuroprotection in pre- and symptomatic preclinical mouse models of AD and aging. These studies suggest that novel strategies to alter mitochondrial energy homeostasis may have profound translational therapeutic potential for AD. Using multiple biochemistry, computational and systems biology approaches, and extensive in vivo translational studies, we developed small molecules that bind next to the flavin mononucleotide redox center of MCI mildly inhibiting its activity. The molecular mechanism of MCI inhibitors impinges on pathways induced by caloric restriction and exercise including activation of AMPK; increased resistance to oxidative stress; enhanced mitochondrial biogenesis, energetics, dynamics and function; reduction of glycogen synthase kinase 3β activity; increased levels of brain-derived neurotrophic factor (BDNF) and synaptic proteins in vivo; a reduction in levels of Aβ and pTau and inflammation ultimately blocking neurodegeneration in AD mice. We have confirmed these effects in a range of systems (primary mouse neurons, multiple mouse models of familial AD, wild-type mice fed with a high fat diet, chronologically aged mice, mitochondria isolated from mouse and human brain, human lymphocytes, fibroblasts and neuronal cells differentiated from human iPSCs), supporting the high translational potential of this approach. The advantages of our molecules include the ability to penetrate the blood brain barrier, low toxicity, in vivo efficacy, and the known molecular target. Based on the target validation and the identification of the molecular mechanism, we developed multiple in vitro and in vivo assays that were used for structure-activity relationship (SAR) studies resulting in the development of a robust Discovery Funnel and arrays of novel series of proprietary compounds MCI inhibitors with promising drug-like properties (US patent granted). We propose to advance our small molecule therapeutics to the clinic by entering the BPN at the Discovery stage where, with the team of the BPN Consultants and CROs, we will progress toward the identification of preclinical and development candidates, and to the submission of the IND application in preparation for a Phase I Clinical Trial.

摘要 阿尔茨海默病（AD）中的异常能量稳态与突触功能障碍相关， 神经变性使用多种系统生物学方法和荟萃分析生成的新兴数据 在AD患者中发现了一个AMP-蛋白激酶（AMPK）整合的信号网络， 线粒体能量生产流，并可在AD中提供神经保护。我们发现部分 抑制线粒体复合物I（MCI）可改善葡萄糖摄取和利用，树突棘成熟， 长时程增强、突触活动、认知功能，并减少Aβ和pTau积累、氧化 应激和炎症导致AD临床前和症状前小鼠模型的神经保护作用 和衰老。这些研究表明，改变线粒体能量稳态的新策略可能具有 对AD的巨大转化治疗潜力。利用多种生物化学，计算和系统 生物学方法和广泛的体内翻译研究，我们开发了小分子， 对MCI的黄素单核苷酸氧化还原中心有轻度抑制作用。MCI的分子机制 抑制剂影响热量限制和运动诱导的途径，包括AMPK的激活; 增加对氧化应激的抵抗力;增强线粒体生物发生、能量学、动力学和 功能;糖原合成酶激酶3β活性降低;脑源性神经营养素水平升高 Aβ和pTau水平的降低和炎症最终导致脑源性神经营养因子（BDNF）和突触蛋白的表达增加。 阻断AD小鼠的神经变性。我们已经在一系列系统中证实了这些效应（主要 小鼠神经元、家族性AD的多种小鼠模型、高脂饮食喂养的野生型小鼠，按时间顺序 老年小鼠、从小鼠和人脑分离的线粒体、人淋巴细胞、成纤维细胞和神经元 从人iPSC分化的细胞），支持该方法的高翻译潜力。的 我们的分子的优点包括穿透血脑屏障的能力，低毒性，体内 有效性和已知的分子靶点。基于目标验证和分子鉴定， 机制，我们开发了多种用于构效关系的体外和体内测定方法， (SAR)研究导致了一个强大的发现漏斗和一系列新的 专利化合物MCI抑制剂，具有类似药物的特性（已授予美国专利）。我们建议 通过在发现阶段进入BPN，将我们的小分子疗法推向临床， 在BPN顾问和CRO团队的帮助下，我们将逐步确定临床前和 开发候选人，并提交IND申请以准备I期临床试验 审判