In vivo Evaluation of USP30 Inhibitors in Models Relevant to Parkinson's Disease

USP30 抑制剂在帕金森病相关模型中的体内评价

• 批准号: 10603217
• 负责人: Bahareh Behrouz
• 金额: $ 47.05万
• 依托单位: VINCERE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603217
• 关键词: Acute; Address; Affect; Age; American; Animal Model; Animals; Automobile Driving; Autopsy; Back; Binding Proteins; Biochemical; Biological Assay; Biological Sciences; Biology; Biotechnology; Brain; Cell Count; Cell Line; Cells; Central Nervous System Diseases; Clinic; Clinical; Clinical Trials; Complex; Corpus striatum structure; Data; Deubiquitinating Enzyme; Development; Disease; Disease Pathway; Disease Progression; Dopamine; Dose; Drosophila genus; Drug Kinetics; Elements; Experimental Designs; FBXO7 gene; Female; Future; Genetic; Genetic Models; Homeostasis; Human; Human Genetics; Idiopathic Parkinson Disease; In Vitro; Investigational Drugs; Investments; Kinetics; Knowledge; LRRK2 gene; Lead; Letters; Licensing; Light; Link; Manuscripts; Measures; Mediating; Methods; Microsomes; Mitochondria; Modeling; Modification; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Oligomycins; Other Genetics; PINK1 gene; Paper; Paraquat; Parkin; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Penetration; Permeability; Persons; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacology; Plasma; Plasma Proteins; Positioning Attribute; Property; Rattus; Regimen; Risk Factors; Rodent; Series; Sex Differences; Solubility; Study models; Substantia nigra structure; Testing; Therapeutic; Tissues; Toxic effect; Toxin; age related; alpha synuclein; antimycin; cell type; clinical development; cytotoxicity; dopaminergic neuron; drug discovery; experimental study; in vitro activity; in vivo; in vivo evaluation; induced pluripotent stem cell; inhibitor; knock-down; lead candidate; male; mitochondrial dysfunction; mouse model; multidisciplinary; nanomolar; neuroprotection; neurotransmission; novel; overexpression; pars compacta; pre-formed fibril; small molecule; small molecule inhibitor; sporadic Parkinson' s Disease; success; ubiquitin isopeptidase

ABSTRACT Existing treatments for Parkinson’s disease (PD), which affects 10 million people worldwide, primarily augment dopaminergic neurotransmission to provide symptomatic benefit. No current therapy can slow or stop the progression of PD. We propose a drug discovery platform to develop small molecules targeting the parkin-USP30 mitophagy pathway, which represents a key regulator of mitochondrial homeostasis. Converging lines of evidence from human genetics, tissue pathology and biochemical studies from sporadic PD patients, and animal model studies indicate that deficits in Mitophagy are a modifiable contributor to PD pathogenesis. Specifically, inhibition or knockdown of the deubiquitinating enzyme USP30 can enhance mitophagy in a variety of cell types and infers neuroprotection in two fruit fly models (pink1 deficiency and paraquat toxicity). However, studies examining neurodegeneration in larger animals such as rodents are an unfilled gap in knowledge that should be addressed prior to development of USP30 inhibitors as therapeutics for PD. In the proposed Aims, we will test the hypothesis that USP30 inhibitor small molecules will protect against neurodegeneration induced by a mitochondrial toxin MPTP, or a-synuclein preformed fibrils – both models with links to Parkinson’s disease and mitophagy. Our preliminary data demonstrate that we have generated a series of small molecules that potently and selectively inhibit USP30 activity in vitro, and demonstrate cellular activity without cytotoxicity in differentiated neuronal cell lines. Top compounds have good in vitro ADME properties and a lead and back up compound have been identified with excellent rat and mouse plasma and brain PK profiles which place us in a unique position to examine the proposed hypothesis. If successful, the studies proposed in this application will justify further investment toward development of our small molecules through Investigational New Drug filing (IND)-enabling studies, out-license, or partnership with big pharma or biotech for further clinical development.

摘要 帕金森病（PD）影响着全球1000万人，现有的治疗方法主要是增加 多巴胺能神经传递以提供症状益处。目前没有任何疗法可以减缓或阻止 PD的进展。我们提出了一个药物发现平台，以开发靶向parkin-USP 30的小分子 线粒体自噬途径，其代表线粒体稳态的关键调节器。汇聚的线条 来自散发性PD患者和动物的人类遗传学、组织病理学和生化研究的证据 模型研究表明线粒体自噬缺陷是PD发病机制的可改变因素。具体地说， 去泛素化酶USP 30的抑制或敲低可以增强多种细胞类型中的线粒体自噬 并在两种果蝇模型（pink 1缺乏和百草枯中毒）中推断出神经保护作用。然而研究 在大型动物如啮齿动物中检查神经变性是一个未填补的知识空白， 在开发USP 30抑制剂作为PD治疗剂之前解决。在提出的目标中，我们将测试 USP 30抑制剂小分子将保护免受神经变性诱导的假设， 线粒体毒素MPTP或α-突触核蛋白形成的纤维-这两种模型都与帕金森病有关， 线粒体自噬我们的初步数据表明，我们已经产生了一系列小分子， 并在体外选择性抑制USP 30活性，并在分化的细胞中显示细胞活性而无细胞毒性。 神经元细胞系顶级化合物具有良好的体外ADME性质，并且先导化合物和备用化合物具有良好的体外ADME性质。 已确定具有出色的大鼠和小鼠血浆和脑PK特征，这使我们处于独特的地位， 检查提出的假设。如果成功，本申请中提出的研究将证明进一步的研究是合理的。 通过研究性新药申请（IND）对我们的小分子开发进行投资-使 研究、许可证发放或与大型制药公司或生物技术公司合作进行进一步的临床开发。