Novel Protein Aggregation Inhibitors and Upper Motor Neuron Stabilizers for ALS and other Neurodegenerative Diseases

用于治疗 ALS 和其他神经退行性疾病的新型蛋白质聚集抑制剂和上运动神经元稳定剂

• 批准号: 10403947
• 负责人: Pembe Hande Ozdinler
• 金额: $ 60.96万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403947
• 关键词: Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Attention; Basic Science; Biological Assay; Biological Process; Biology; Brain; Cells; Characteristics; Chemistry; Clinical Trials; Collaborations; Cyclohexanes; Development; Disease; Disease model; Drug Kinetics; Drug Screening; FDA approved; Genetic; Goals; Grant; Health; Hereditary Spastic Paraplegia; Impairment; In Vitro; Label; Laboratories; Measures; Modeling; Motor; Motor Neuron Disease; Motor Neurons; Movement; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; PC12 Cells; Parkinson Disease; Pathology; Pathway interactions; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Photoaffinity Labels; Population; Preclinical Drug Development; Preclinical Testing; Primary Lateral Sclerosis; Process; Property; Proteasome Inhibition; Proteins; Pyrazolones; Reporter; Research; Science; Structure; Therapeutic; Toxic effect; Translating; Translations; Upper Motor Neuron Disease; age related; age related neurodegeneration; analog; base; covalent bond; design; drug candidate; drug discovery; effective therapy; experimental study; frontotemporal lobar dementia-amyotrophic lateral sclerosis; improved; in vivo; inhibitor; innovation; interest; motor neuron function; multicatalytic endopeptidase complex; mutant; neuron loss; neuropathology; novel; novel strategies; novel therapeutics; overexpression; phenylmethylpyrazolone; pre-clinical; preclinical evaluation; preclinical study; protein aggregation; response; scaffold; screening; superoxide dismutase 1

Abstract: Recent developments in chemistry, genetics, and biology revealed that many of the age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and ALS/FTD share protein accumulation as the common cause of neuropathology. In addition, the number and kinds of compounds generated within the last years have exponentially increased. However, these developments in science have not yet successfully translated into effective drug discoveries for patients. This proposal is a collaborative project between the Silverman and Ozdinler Labs, blending expertise in medicinal chemistry and selective neuronal vulnerability, respectively. In an effort to expedite drug discovery and to identify novel compounds that can move into clinical trials for ALS and age-related disorders, which develop in part because of protein aggregation, such as Alzheimer's disease, we have developed a novel strategy and a strong team effort. This strategy also could, more broadly, ameliorate other neurodegenerative diseases in which voluntary movement is affected and in which protein aggregation is a major underlying cause. Dr. Silverman discovered several compounds that inhibit protein aggregation in cells and that have favorable pharmacokinetic properties, and Dr. Ozdinler developed a novel in vitro and in vivo preclinical drug screening/verification platform using the improved health of upper motor neurons (UMNs) that become diseased from different underlying factors, as the read-out. Recent discoveries from the Ozdinler group reveal the importance of improving UMN health early in the disease and that maintaining UMN health is crucial for effective drug discovery efforts. It is unfortunate that this important neuron population has never before been considered in preclinical studies, even for diseases that are identified by their selective and progressive degeneration. This proposal will develop the first preclinical platform that utilizes diseased UMNs for the assessment of novel compounds generated in the Silverman lab that inhibit protein aggregation and improve the health of diseased UMNs both in vitro and in vivo. Upon completion of this proposal, we will move the field forward along two different avenues by developing a new preclinical assay that incorporates UMN health as the read-out, and by identifying novel drugs for age-related neurodegenerative diseases that develop from problems with protein aggregation .

抽象的： 化学、遗传学和生物学的最新进展表明，许多与年龄相关的神经退行性疾病 肌萎缩侧索硬化症 (ALS)、阿尔茨海默病和 ALS/FTD 等疾病共享蛋白质 积累是神经病理学的常见原因。另外，化合物的数量和种类 近年来产生的数量呈指数级增长。然而，这些科学发展并没有 但却成功转化为对患者有效的药物发现。该提案是一个合作项目 Silverman 和 Ozdinler 实验室之间，融合了药物化学和选择性神经元方面的专业知识 分别是脆弱性。为了加快药物发现并识别可以移动的新化合物 进入 ALS 和年龄相关疾病的临床试验，这些疾病的发展部分是由于蛋白质聚集，例如 针对阿尔茨海默病，我们制定了新颖的策略和强大的团队努力。该策略还可以， 更广泛地说，改善随意运动受到影响的其他神经退行性疾病 其中蛋白质聚集是一个主要的根本原因。西尔弗曼博士发现了几种抑制 Ozdinler 博士开发了一种蛋白质在细胞内聚集并具有良好的药代动力学特性的药物 利用改善上运动健康的新型体外和体内临床前药物筛选/验证平台 正如读数所示，由于不同潜在因素而患病的神经元（UMN）。最近的发现 来自 Ozdinler 小组的研究揭示了在疾病早期改善 UMN 健康状况以及维持健康的重要性 UMN 健康对于有效的药物发现工作至关重要。不幸的是，这个重要的神经元群体 以前从未在临床前研究中考虑过，即使对于通过其选择性确定的疾病也是如此。 和进行性退化。该提案将开发第一个利用患病 UMN 的临床前平台 用于评估西尔弗曼实验室产生的抑制蛋白质聚集的新型化合物 改善患病 UMN 的体外和体内健康状况。完成该提案后，我们将把 通过开发一种新的临床前检测，将UMN健康纳入其中，沿着两条不同的途径向前发展 读出，并通过识别新药来治疗与年龄相关的神经退行性疾病，这些疾病是由 蛋白质聚集问题。