Novel Approaches for Tau PROTAC Drug Discovery

Tau PROTAC 药物发现的新方法

• 批准号: 10697547
• 负责人: Karteek Kadimisetty
• 金额: $ 125.45万
• 依托单位: LIFESENSORS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697547
• 关键词: Academia; Acceleration; Affect; Alzheimer' s Disease; Alzheimer' s disease therapy; Amyotrophic Lateral Sclerosis; Antibody Therapy; Antineoplastic Agents; Autophagocytosis; Autophagosome; Binding; Brain region; Cell Death; Cell model; Cells; Chromatin; Clinic; Complex; Consumption; Cullin Proteins; Data; Development; Disease; Family; Frontotemporal Dementia; G-Protein-Coupled Receptors; Gel; Goals; Grant; Histones; Human; Industry; Ligands; Ligase; Lysosomes; MDM2 gene; Mediating; Membrane Proteins; Methods; Mitochondria; Modality; Modeling; Monitor; Monoubiquitination; Morphologic artifacts; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Nucleosomes; Parkinson Disease; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Polyubiquitin; Polyubiquitination; Progress Reports; Progressive Supranuclear Palsy; Protac; Proteins; Proteome; Recycling; Reporter Genes; Research; Research Personnel; Resistance; Revlimid; Role; Signal Transduction; Specificity; System; Tauopathies; Technology; Testing; Thalidomide; Time; Ubiquitin; Ubiquitination; Western Blotting; abeta accumulation; analog; chimera drug; design; drug discovery; hyperphosphorylated tau; induced pluripotent stem cell; infancy; member; misfolded protein; monomer; multicatalytic endopeptidase complex; mutant; nerve stem cell; novel; novel drug class; novel strategies; novel therapeutics; overexpression; paired helical filament; pre-clinical; protein aggregation; protein degradation; protein transport; rapid technique; screening; small molecule; success; tau Proteins; tau aggregation; tau mutation; technology development; ubiquitin-protein ligase

Novel Approaches for Tau PROTAC Drug Discovery Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) are a group of neurodegenerative diseases characterized by the pathological accumulation of hyper-phosphorylated tau (P-tau) protein, in the form of intracellular paired helical filaments (PHFs) or neurofibrillary tangles (NFTs), or aggregates, within neurons and glia of affected brain regions, leading to cell death. Several approaches to remove aggregates of pathogenic tau have failed, including antibody therapy. Novel approaches to remove aggregated proteins are desired. Targeted protein degradation by PROteolysis TArgeting Chimeras (PROTACs) has emerged as novel therapeutic modality. PROTACs are heterobifunctional small molecules that simultaneously bind to a target protein and a ubiquitin E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present a new opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. PROTAC drugs offer many advantages, such as: 1) target can be selectively degraded with catalytic specificity; 2) weak binders can be converted into selective PROTAC drugs; 3) overexpressed or mutant targets can be degraded; and 4) limited target engagement can lead to maximal degradation. Although most misfolded and aggregated proteins in the human proteome can be degraded by proteasomal system, some native and mutant proteins prone to aggregation, such as tau oligomers are resistant to all known proteolytic pathways thus subject to autophagic or lysosomal pathway. Development of PROTACs that can efficiently degrade pathogenic tau aggregates is an attractive and breakthrough therapy for AD and FTD. No one, industry or academia has shown credible data for tau PROTACs to succeed in the clinic. Traditional methods for PROTAC analysis, western blot or reporter gene analysis are time consuming, cumbersome, and prone to artifacts. In this proposal we describe a high throughput method for rapid development of tau PROTACs. Development of PROTACs that promote tau degradation by lysosomal/autophagic mechanism is challenging. This grant proposes strategies to screening different E3 ubiquitin ligases for tau PROTAC that will remove pathogenic (monomeric) as well as aggregates through autophagic mechanism. Goal of the project is to establish rules that govern pathogenic tau degradations, such as poly-ubiquitin signatures conjugated on tau aggregates to differentiate proteasomal vs lysosomal degradation. Development of the technology that degrades tau aggregates can be directly applied to Parkinson’s disease, Huntingdon disease and Amyotrophic Lateral Scleroses.

Tau PROTAC药物发现的新方法 阿尔茨海默氏病（AD）、额颞叶痴呆（FTD）、进行性核上性麻痹（PSP）是一组 以过度磷酸化的tau（P-tau）的病理性积累为特征的神经变性疾病 蛋白质，以细胞内成对螺旋丝（PHF）或神经纤维缠结（NFT）的形式，或聚集体， 在受影响的大脑区域的神经元和神经胶质中，导致细胞死亡。几种去除骨料的方法 包括抗体治疗在内的治疗方法都失败了。去除聚集蛋白的新方法是 需要的话通过蛋白质水解靶向嵌合体（PROTAC）的靶向蛋白质降解已经成为一种新的方法， 治疗方式PROTAC是异双功能小分子，其同时结合靶点 蛋白和泛素E3连接酶，从而导致靶的泛素化和随后的降解。 它们提供了一个新的机会，以不依赖于酶或信号活性的方式调节蛋白质。 PROTAC药物具有许多优点，如：1）靶点可选择性降解，具有催化特异性; 2)弱结合剂可以转化为选择性PROTAC药物; 3）过表达或突变的靶点可以被 退化;以及4）有限的目标接合可导致最大退化。虽然大多数错误折叠， 人蛋白质组中聚集的蛋白质可以被蛋白酶体系统降解，一些天然的和突变的 易于聚集的蛋白质，例如tau寡聚体，对所有已知的蛋白水解途径具有抗性，因此受到 自噬或溶酶体途径。开发可有效降解致病性tau蛋白的PROTAC 聚合物是治疗AD和FTD的一种有吸引力的突破性疗法。没有人，工业界或学术界已经表明， tau蛋白PROTAC在临床上取得成功的可靠数据。传统的PROTAC分析方法，蛋白质印迹 或报道基因分析是耗时、麻烦的，并且易于产生伪像。在本提案中，我们描述了 用于快速开发tau PROTAC的高通量方法。开发促进tau蛋白的PROTAC 通过溶酶体/自噬机制的降解具有挑战性。该补助金提出了筛查策略 用于tau蛋白PROTAC的不同E3泛素连接酶，其将去除致病性（单体）以及聚集体 通过自噬机制。该项目的目标是建立管理致病性tau蛋白降解的规则， 例如缀合在tau聚集体上的多聚泛素标记以区分蛋白酶体与溶酶体 降解降解tau聚集体的技术的发展可以直接应用于帕金森氏症 亨廷顿病和肌萎缩侧索硬化症。