Development of Cellular HTS for 20S Proteasome Enhancers

目前还没有有效的治疗神经退行性疾病的方法，包括帕金森氏病(PD)， 阿尔茨海默病(AD)和阿尔茨海默氏症相关痴呆(ADRD)。寻找Small的一个主要障碍 能够对抗这些联核病和变态核病的分子是介导 这些障碍在结构上是展开的(即本质上无序)。除了它们聚集的倾向之外 一旦积累，本质上无序的蛋白质缺乏明确的结合口袋，因此它们在很大程度上 避开了传统的药物发现设计努力。然而，最近的研究发现，增强蛋白酶体 活性可以防止内在无序蛋白质(如α-突触核蛋白和tau)的有毒积聚 物种)，减少脑损伤，预防AD相关痴呆。不同的蛋白酶体复合体， 只有20年代的蛋白酶体直接降解的靶标本质上是无序的。不幸的是， 这一全新的治疗策略的翻译探索受到限制，原因是(1)缺乏 适合鉴定20S蛋白酶体增强子的细胞试验，以及随后的，(2)缺乏类药物小分子 分子20S蛋白酶体增强剂。 这笔赠款将直接解决目前阻碍这种新疗法探索的这两个空白 帕金森病、阿尔茨海默病和不良反应的治疗策略。在R61阶段，我们将开发和验证第一个细胞和 与生理相关的高通量筛查(HTS)分析，目标是扩大小型 20s蛋白酶体的分子类药物增强剂。在R33阶段，我们将优化疗效和 从筛选中选择两个系列的物理化学性质，以产生用于 对这一新方法的翻译探索。 这项工作的成功完成将为识别和开发合适的类药物提供一个强有力的平台 探索这一治疗帕金森氏症新方法的翻译潜力的候选人 阿尔茨海默病、阿尔茨海默病和阿尔茨海默病相关的痴呆。

There are still no effective treatments for neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD) and Alzheimer’s related dementias (ADRD). One major obstacle in finding small molecules capable of combatting these synucleinopathies and tauopathies is that the proteins that mediate these disorders are structurally unfolded (i.e. intrinsically disordered). In addition to their tendency to aggregate upon accumulation, intrinsically disordered proteins lack defined binding pockets, thus they have largely evaded traditional drug discovery design efforts. However, recent studies found that enhancing proteasome activity can prevent toxic accumulation of intrinsically disordered proteins (such as α-synuclein and tau species), reduce brain damage and prevent AD related dementia. Of the different proteasome complexes, only the 20S proteasome targets intrinsically disordered directly for degradation. Unfortunately, the translational exploration of this entirely new therapeutic strategy has been limited due to (1) the lack of a suitable cellular assay to identify 20S proteasome enhancers and subsequently, (2) lack of drug-like small molecule 20S proteasome enhancers. This grant will directly address these two voids that currently prevent the exploration of this new therapeutic strategy to treat PD, AD and ADRDs. In the R61 phase, we will develop and validate the first cellular and physiologically relevant high throughput screening (HTS) assays with the goal to broaden the portfolio of small molecule drug-like enhancers of the 20S proteasome. In the R33 phase, we will optimize the efficacy and physiochemical properties of two select series from that screen to generate the first suitable agents for the translational exploration of this new approach. Successful completion of this work will provide a robust platform to identify and develop suitable drug-like candidates to explore the translational potential of this new therapeutic approach for treating Parkinson’s disease, Alzheimer’s disease and Alzheimer’ related dementias.