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。

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要/摘要拟议的第一阶段研究旨在确定技术/科学优点和可行性开发首个/同类最佳的 USP30 抑制剂，用于治疗帕金森病 (PD)，这是一种年龄相关的神经退行性疾病的患病率仅次于阿尔茨海默病（AD）。无治疗方法。目前存在可以减缓或阻止 PD 进展的药物，可影响 10 人。全球有数百万人，仅仅增强多巴胺能神经传递即可提供症状益处。为了解决这一未满足的需求，Vincere Biosciences 启动了一个开发小分子的平台靶向 Parkin-USP30 泛素化途径，该途径代表线粒体的关键调节因子体内平衡，作为减缓疾病进展的一种手段——人类。药理学、遗传学、组织病理学和动物模型研究——表明线粒体缺陷质量控制途径是 PD 病原体的基础，而 Parkin（一种 E3 泛素连接酶）通过以下方式驱动线粒体自噬。 USP30 将泛素链添加到受损线粒体上的蛋白质中，去除这些链以抑制清除受损的线粒体，从而充当帕金阳的阴。值得注意的是，功能基因组。对哺乳动物细胞和果蝇的研究已验证 USP30 是线粒体质量控制的关键目标。虽然线粒体异常长期以来一直与散发性帕金森病有关，但有令人信服的科学依据现在也可用于恢复 AD 中的线粒体健康。通过抑制 USP30，我们的目标是间接增强。 Parkin 的下游信号传导，增加线粒体自噬并恢复线粒体，从而恢复稳态。这样做，我们将检验 USP30 抑制剂促进受损细胞清除的假设线粒体，从而减弱与 PD 发病机制相关的致病级联反应。我们已经鉴定出几种能够在体外有效抑制 USP30 活性的热门化合物，并证明此外，我们的初步数据令人兴奋。表明我们有严格的流程分析并开始使用化学支架来提供：两个具有先导物优化 IP 潜力的独特先导物系列（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) 和目标调节/功效评估和临床前开发（目标 2）。在拟议的第一阶段研究中，我们将回答以下技术问题：1）我们能否确定具有足够选择性的有效且可申请专利的 USP30 抑制剂；2) 诱导人体细胞线粒体自噬没有细胞毒性和基础线粒体膜电位的影响，并且，3) 在体外显示出所需的效果； ADME 特性旨在实现体内概念研究验证和阶段性临床前开发 II？未来的 II 期将通过体内 PK、PK-药效 (PK-PD) 研究来进行这些分子，和临床前开发（研究性新药（IND）支持研究）来定位我们的分子，与大型制药/生物技术公司的许可或合作伙伴关系，他们已经对我们的项目表示了兴趣。