Caspase-2 Probe Compounds

Caspase-2 探针化合物

基本信息

批准号：
10532777
负责人：
Karen H Ashe
金额：
$ 70.96万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532777
关键词：
AMPA Receptors Acceleration Alzheimer&apos s Disease Alzheimer&apos s disease brain Animal Model Binding Biological Assay Biological Markers Biological Models Biology Brain CASP2 gene Caspase Cells Chemicals Cognition Cognitive Cognitive deficits Collection Communities Crystallography Cytoskeletal Proteins Dendritic Spines Development Docking Family Frontotemporal Dementia Functional disorder Glaucoma Goals Health Human Huntington Disease Huntington gene Impaired cognition In Vitro Industry Standard Measurement Measures Mediating Modeling Modification Molecular Mus National Center for Advancing Translational Sciences Nerve Degeneration Neuroblastoma Neurodegenerative Disorders Neurologic Neurons Oxidative Stress Parkinson Disease Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Postsynaptic Membrane Proteins Proteolysis Research Research Personnel Role Scientist Series Site Specificity Stroke Structure-Activity Relationship Synapses Synaptic Transmission Synaptic plasticity System Tauopathies Testing Therapeutic Translational Research United States National Institutes of Health Visualization Work aged analog clinically relevant cognitive function design disease phenotype drug-like compound excitotoxicity follow-up improved in vivo in vivo Model inhibitor innovation meter morris water maze multidisciplinary mutant nervous system disorder neurophysiology novel therapeutics pharmacologic postsynaptic preclinical study preservation prevent receptor function repaired side effect small molecule structural biology synaptic function tau Proteins therapeutic development therapeutic target tool transgene expression

项目摘要

Project Summary Abstract Caspase-2 has been implicated in neurological indications such as stroke, Alzheimer's, Parkinson's, and Huntington's diseases, neuroblastoma, neuro-ophthalomology, and frontotemporal dementia. The broad, long- term objective of our work is the development of specific caspase-2 inhibitors as neuro-therapeutic agents. This long-term objective hinges on first developing caspase-2 probes that will allow us to show that specific pharmacological reduction of caspase-2 activity by small molecule probes leads to the amelioration of disease phenotype, initially in animal models. Our specific aims all target the discovery and development of caspase-2 probes but each has a different starting point. We will use measurement of ∆tau314 levels, a specific therapeutically- and clinically-relevant biomarker, as part of our testing funnel, to gauge the efficacy of our probes in cells. Our probe design and development will feature three parallel paths of compound characterization and optimization, each of which will inform the other as to caspase-2 binding that influences specificity and potency. Our three aims are to develop (1) probes from proteins that are specifically cleaved by caspase-2, (2) probes from HTS follow-on, and (3) probes from known selective caspase-2 inhibitors. Our goal in each of these is to produce a probe or tool compound which has in vitro potency <100 nM at the target protein, possesses >30-fold selectivity relative to sequence-related targets in the same family, has been profiled against an “industry- standard” panel of pharmacologically-relevant off-targets, and has demonstrated on-target effect in cells of <1 µM. To demonstrate in vivo relevance, we will test these probes in rTg4510 mice using the Morris water maze, a well-established model of cognition. We expect that these probes that specifically target caspase-2 will restore cognition in these aged mice without observable side effects. Ultimately, we will use these specific caspase-2 probes to investigate the broad range of neurological disorders in which caspase-2 activity has been implicated. This will constitute and important vertical advancement and spur the pharmaceutical development of therapeutics that will positively impact human health.

项目摘要摘要 caspase-2已在中风，阿尔茨海默氏症，帕金森氏症和亨廷顿的疾病，神经母细胞瘤，神经 - 脑疾病学和额颞痴呆。宽阔，长期我们工作的术语目标是开发特定的caspase-2抑制剂作为神经治疗剂。这长期目标取决于首先开发caspase-2问题，这将使我们能够表明该特定小分子问题对caspase-2活性的药理减少导致疾病的改善表型，最初是在动物模型中。我们的具体目的都是针对caspase-2的发现和开发问题，但每个都有一个不同的起点。我们将使用∆TAU314级别的测量作为我们的测试漏斗的一部分，在治疗和临床上与临床相关的生物标志物，以评估我们的问题的效率在细胞中。我们的探针设计和开发将具有复合表征的三个平行路径和优化，每种都会告知对方的caspase-2结合，从而影响特异性和效力。我们的三个目的是从蛋白质特定裂解的蛋白质中提出（1）问题，（2）问题来自HTS后续的，（3）已知的选择性caspase-2抑制剂的问题。我们在这些目标中的目标是产生探针或工具化合物，其在靶蛋白上的体外效力<100 nm，具有> 30倍相对于同一家庭中与序列相关目标的选择性相对于序列相关的目标，已针对“行业 - 标准”的药物与脱靶相关的面板，并且在细胞<1的细胞中表现出靶向效应 µm。为了证明体内相关性，我们将使用Morris Water Maze在RTG4510小鼠中测试这些问题，一个认知的模型。我们希望这些专门针对caspase-2的问题将恢复这些老年小鼠的认知没有可观察到的副作用。最终，我们将使用这些特定的caspase-2 研究caspase-2活性的广泛神经系统疾病的探针。这将构成重要的垂直进步，并刺激治疗的药物开发这将对人类健康产生积极影响。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.

DOI：
10.1002/ardp.202200095
发表时间：
2022-09
期刊：
ARCHIV DER PHARMAZIE
影响因子：
5.1
作者：
Bresinsky, Merlin;Strasser, Jessica M.;Hubmann, Alexander;Vallaster, Bernadette;McCue, William M.;Fuller, Jessica;Singh, Gurpreet;Nelson, Kathryn M.;Cuellar, Matthew E.;Finzel, Barry C.;Ashe, Karen H.;Walters, Michael A.;Pockes, Steffen
通讯作者：
Pockes, Steffen

Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy.

DOI：
10.1021/acschemneuro.2c00100
发表时间：
2022-05-18
期刊：
ACS CHEMICAL NEUROSCIENCE
影响因子：
5
作者：
Singh, Gurpreet;Liu, Peng;Yao, Katherine R.;Strasser, Jessica M.;Hlynialuk, Chris;Leinonen-Wright, Kailee;Teravskis, Peter J.;Choquette, Jessica M.;Ikramuddin, Junaid;Bresinsky, Merlin;Nelson, Kathryn M.;Liao, Dezhi;Ashe, Karen H.;Walters, Michael A.;Pockes, Steffen
通讯作者：
Pockes, Steffen