Discovery and Development of USP30 inhibitors as Disease-Modifying Therapy for Parkinson's disease.

USP30 抑制剂的发现和开发作为帕金森病的疾病缓解疗法。

• 批准号: 10007274
• 负责人: Bahareh Behrouz
• 金额: $ 25.2万
• 依托单位: VINCERE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007274
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Animal Model; Attenuated; Back; Biological Assay; Biological Sciences; Biology; Biotechnology; Cells; Chemicals; Cognitive deficits; Coupled; Data; Development; Disease; Disease Progression; Drug Kinetics; Engineering; Ensure; Fibroblasts; Future; Genetic; Glean; Health; Homeostasis; Human; In Vitro; Investigational Drugs; Lead; Length; Letters; Licensing; Mammalian Cell; Membrane Potentials; Mitochondria; Motor; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Positioning Attribute; Prevalence; Process; Program Development; Property; Proteins; Quality Control; Quality of life; Reporting; Research; Scheme; Signal Transduction; Source; Specificity; Structural Chemistry; Structure-Activity Relationship; Study models; Testing; Tissues; Toxic effect; Ubiquitin; Ubiquitination; Yang; Yin; base; clinical development; computational chemistry; cytotoxicity; design; disability; enzyme activity; fly; functional genomics; improved; in vitro activity; in vivo; inhibitor/antagonist; insight; interest; lead optimization; lead series; mitochondrial membrane; multidisciplinary; neurotransmission; non-motor symptom; parkin gene/protein; phase 1 study; phase 2 study; preclinical development; programs; research and development; scaffold; small molecule; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT The proposed Phase I research is designed to establish the technical/scientific merit and feasibility of developing first/best-in-class, USP30 inhibitors for the treatment of Parkinson’s disease (PD), an age- associated neurodegenerative disorder second only to Alzheimer’s disease (AD) in prevalence. No therapy that can slow or stop the progression of PD currently exists. Instead, treatments for PD, which affects 10 million people worldwide, merely augment dopaminergic neurotransmission to provide symptomatic benefit. To address this unmet need, Vincere Biosciences has initiated a platform to develop small molecules targeting the parkin-USP30 ubiquitination pathway, which represents a key regulator of mitochondrial homeostasis, as a means of slowing disease progression. Converging lines of evidence – human pharmacology, genetics, tissue pathology and animal model studies – indicate that deficits in mitochondrial quality control pathways underlie PD pathogenes. While parkin, an E3 ubiquitin ligase, drives mitophagy by adding ubiquitin chains to proteins on damaged mitochondria, USP30 removes these chains to inhibit clearance of the damaged mitochondria, thus acting as the yin to parkin’s yang. Of note, functional genomic studies in mammalian cells and flies have validated USP30 as a key target of mitochondrial quality control. While mitochondrial abnormalities have long been implicated in sporadic PD, compelling scientific rationale also now exists for restoring mitochondrial health in AD. By inhibiting USP30, we aim to indirectly enhance parkin’s downstream signaling, thereby increasing mitophagy and restoring mitochondrial homeostasis. In so doing, we will test the hypothesis that USP30 inhibitors promote the clearance of damaged mitochondria, thereby attenuating the pathogenic cascade associated with PD pathogenesis. We have identified several hit compounds that potently inhibit USP30 activity in vitro, and demonstrate cellular activity without cytotoxicity in human primary fibroblast cells. Moreover, our exciting preliminary data indicate that we have rigorous flow scheme assays and starting chemical scaffolds in place to deliver: two distinct lead series with IP potential for lead optimization (Aim 1); and, up to 12 optimized compounds for further in vivo pharmacokinetic (PK) and target modulation/efficacy assessment and preclinical development (Aim 2). In the proposed Phase I studies, we will answer the following technical questions: 1) Can we identify potent and patentable USP30 inhibitors with sufficient selectivity; that, 2) Induce mitophagy in human cells without cytotoxicity and effects of basal mitochondrial membrane potential; and, 3) Display desired in vitro ADME properties engineered to enable in vivo proof of concept studies and preclinical development in Phase II? A future Phase II will carry these molecules through in vivo PK, PK-Pharmacodynamic (PK-PD) research, and preclinical development (Investigational New Drug (IND)-enabling studies) to position our molecules, for out-license or partnership with big pharma/biotech, who have already expressed interest in our program.

项目总结/摘要 拟议的第一阶段研究旨在确定以下技术/科学价值和可行性： 开发用于治疗帕金森病（PD）的首个/同类最佳USP 30抑制剂， 相关的神经退行性疾病的患病率仅次于阿尔茨海默病（AD）。无治疗 可以减缓或阻止PD进展的药物。相反，PD的治疗，影响10 全世界数百万人，仅仅是增加多巴胺能神经传递以提供症状益处。 为了解决这一未满足的需求，Biosciences启动了一个开发小分子的平台， 靶向parkin-USP 30泛素化途径，这是一个关键的调节线粒体 稳态，作为减缓疾病进展的手段。汇聚的证据线-人类 药理学、遗传学、组织病理学和动物模型研究表明， 质量控制途径是PD病因的基础。而parkin，一种E3泛素连接酶， 通过将泛素链添加到受损线粒体上的蛋白质中，USP 30去除这些链以抑制 清除受损的线粒体，从而充当帕金氏阳的阴。值得注意的是，功能基因组 在哺乳动物细胞和果蝇中的研究已经证实USP 30是线粒体质量控制的关键靶标。 虽然线粒体异常长期以来与散发性PD有关，但令人信服的科学依据 现在也存在用于恢复AD中的线粒体健康。通过抑制USP 30，我们的目标是间接增强 帕金的下游信号，从而增加线粒体自噬和恢复线粒体稳态。这样 这样做，我们将测试的假设，USP 30抑制剂促进清除受损的 线粒体，从而减弱与PD发病机制相关的致病级联。 我们已经鉴定了几种在体外有效抑制USP 30活性的命中化合物，并证明 在人原代成纤维细胞中无细胞毒性的细胞活性。此外，我们令人兴奋的初步数据 这表明我们有严格的流程分析和开始的化学支架，以提供：两个 具有IP潜力的不同铅系列，用于铅优化（目标1）;以及多达12种优化化合物， 进一步的体内药代动力学（PK）和靶向调节/疗效评估和临床前开发 (Aim 2）。在拟议的第一阶段研究中，我们将回答以下技术问题：1）我们能否识别 具有足够选择性的有效且可申请专利的USP 30抑制剂; 2）在人类细胞中诱导线粒体自噬 没有细胞毒性和基础线粒体膜电位的影响;和，3）体外显示所需的 ADME特性经过设计，可用于体内概念验证研究和临床前开发阶段 二？未来的II期将通过体内PK，PK-药效学（PK-PD）研究， 和临床前开发（研究性新药（IND）-使能研究），以定位我们的分子， 与已经对我们的计划表示兴趣的大型制药/生物技术公司合作或合作。