Novel Approaches for Tau PROTAC Drug Discovery

Tau PROTAC 药物发现的新方法

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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），额颞痴呆（FTD），进行性上腹部麻痹（PSP）是一组神经退行性疾病以高磷酸化TAU（P-TAU）的病理积累为特征蛋白质，以细胞内配对的螺旋丝（PHF）或神经原纤维缠结（NFTS）或聚集体的形式在受影响的大脑区域的神经元和神经元内导致细胞死亡。删除聚合的几种方法致病性TAU的失败，包括抗体疗法。去除聚合蛋白质的新方法是需要。靶向嵌合体（Protac）靶向蛋白质降解已成为新颖的治疗方式。 protac是异性功能的小分子，仅结合目标蛋白质和泛素E3连接酶，从而导致靶标的泛素化和随后的降解。他们提供了一个新的机会，以独立于酶促或信号活性的方式调节蛋白质。 Protac药物具有许多优势，例如：1）靶标可以选择性地降解催化特异性； 2）可以将弱粘合剂转化为选择性的protac药物； 3）过表达或突变目标可以是退化； 4）有限的目标参与会导致最大降解。虽然大多数错误，并且人蛋白质组中的综合蛋白可以通过蛋白酶体系统降解，一些天然和突变体易于聚集的蛋白质，例如tau低聚物对所有已知的蛋白水解途径具有抗性到自噬或溶酶体途径。开发可以有效降解致病性tau的Protac 聚集体是AD和FTD的一种有吸引力的突破性疗法。没有人，行业或学术界已经表明 tau protac在诊所取得成功的可靠数据。传统的Protac分析方法，Western印迹或记者基因分析耗时，繁琐且容易产生工件。在这个建议中，我们描述 tau protac快速发展的高通量方法。开发促进tau的protac 溶酶体/自噬机制降解是挑战。审查提案策略筛查 Tau Protac的不同E3泛素连接酶，将去除病原（单体）以及聚集体通过自噬机制。该项目的目标是建立控制致病性tau降解的规则，例如在tau聚集体上结合的多泛素特征，以区分蛋白酶体与溶酶体降解。可以直接应用于帕金森氏症的技术的开发降低tau聚集体的技术疾病，亨廷顿疾病和肌萎缩性侧索硬化症。