Multiparameter optimization of new phenothiazines for proteasome activation

新型吩噻嗪类蛋白酶体激活的多参数优化

• 批准号: 10084217
• 负责人: JETZE J. TEPE
• 金额: $ 22.01万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084217
• 关键词: Address; Affect; Alzheimer' s Disease; Binding; Binding Proteins; Brain; Cell Culture Techniques; Cells; Chemicals; Chlorpromazine; Disease; Dopamine Antagonists; Dopamine Receptor; Drug Design; Goals; Grant; Guidelines; Health; Human; In Vitro; Lead; Metabolic; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Permeability; Pharmaceutical Preparations; Phenothiazines; Property; Proteins; Regulation; Reporting; Science; Signal Transduction; Signaling Molecule; Solubility; Structural Protein; Structure; Symptoms; Therapeutic; Toxic effect; Translations; Work; alpha synuclein; chemical property; drug discovery; high throughput screening; in vivo; lead optimization; multicatalytic endopeptidase complex; novel therapeutic intervention; polyglutamine; scaffold; small molecule; superoxide dismutase 1; symptom treatment; tau Proteins; three dimensional structure

There are no treatment options for neurodegenerative diseases such as Alzheimer’s disease (AD). Current treatments only temporarily suppress disease symptoms. We are pioneering a new paradigm in drug discovery that involves activation of the 20S proteasome, which targets specific proteins associated in the pathogenesis of neurodegenerative diseases. The translation of this therapeutic approach has been largely unexplored due to the lack of suitable leads. This work addressed that void. Our lab identified the most potent 20S activator reported to date. The hit compound activates the proteolytic activity of the 20S proteasome (~10 fold!) and induces the degradation of alpha-synuclein and tau (most notable protein involved in the pathogenesis of AD) in vitro and cell culture without affecting normal structured proteins. We hypothesize that optimization focused on both potency and physicochemical properties will allow us to generate the first 20S activator with drug-like properties suitable for in vivo translation of this new therapeutic strategy for neurodegenerative diseases. In this exploratory R21 grant, we will complete a multiparameter optimization effort by (1) hit-to- lead optimization of potency, and (2) physicochemical optimization of the phenothiazine scaffold to generate drug-like candidates with suitable parameters for CNS chemical space. Successful completion of this work will generate suitable drug-like candidates to explore an entirely new therapeutic approach that targets a unique class of proteins still deemed, undruggable.

对于神经退行性疾病，如阿尔茨海默病（AD），目前还没有治疗方案。目前的治疗只能暂时抑制疾病症状。我们正在开拓一种新的药物发现模式，涉及激活20S蛋白酶体，该蛋白酶体针对与神经退行性疾病发病机制相关的特定蛋白质。由于缺乏合适的引线，这种治疗方法的翻译在很大程度上未被探索。这项工作解决了这个空白。