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

项目摘要/摘要 拟议的第一阶段研究旨在确定技术/科学价值和可行性 开发用于治疗帕金森病(PD)的一流/同类最佳的USP30抑制剂，这是一个年龄- 相关神经退行性疾病的发病率仅次于阿尔茨海默病(AD)。没有治疗方法 可以延缓或阻止帕金森病进展的药物目前已经存在。相反，帕金森氏症的治疗，它影响10 全世界有数百万人，只是为了提供症状益处而增加多巴胺能神经传递。 为了解决这一未得到满足的需求，Vincere生物科学公司发起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 动态平衡，作为减缓疾病进展的一种手段。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--表明线粒体缺陷 质量控制途径是帕金森病发病机制的基础。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上，USP30移除这些链以抑制 清除受损的线粒体，从而起到阴阳的作用。值得注意的是，功能基因组 对哺乳动物细胞和果蝇的研究证实，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，但令人信服的科学依据 现在也存在恢复AD患者线粒体健康的方法。通过抑制USP30，我们的目标是间接增强 Parkin的下游信号转导，从而增加有丝分裂，恢复线粒体的动态平衡。在苏中 这样做，我们将检验USP30抑制剂促进损伤清除的假设 线粒体，从而减轻与帕金森病发病相关的致病级联反应。 我们已经确定了几种在体外能够有效抑制USP30活性的热门化合物，并证明了 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 表明我们有严格的流动方案分析和启动化学支架来交付：两个 独特的铅系列，具有铅优化的IP潜力(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 (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和专利的USP30抑制剂；2)诱导人类细胞的有丝分裂 没有细胞毒性和基础线粒体膜电位的影响；以及，3)体外展示所需的 ADME特性设计为能够在体内进行概念验证研究和临床前阶段开发 二号？未来的第二阶段将通过体内PK，PK-药效学(PK-PD)研究携带这些分子， 和临床前开发(研究新药(IND)-使研究成为可能)来定位我们的分子， 获得许可或与大型制药/生物技术公司合作，后者已经表示对我们的计划感兴趣。

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.