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.

项目概要摘要 Caspase-2 与中风、阿尔茨海默病、帕金森病等神经系统疾病有关亨廷顿舞蹈病、神经母细胞瘤、神经眼科和额颞叶痴呆。我们工作的长期目标是开发特定的 caspase-2 抑制剂作为神经治疗剂。长期目标取决于首先开发 caspase-2 探针，这将使我们能够证明特定的通过小分子探针药理学降低 caspase-2 活性可改善疾病表型，最初是在动物模型中，我们的具体目标都是针对 caspase-2 的发现和开发。探针，但每个都有不同的起点，我们将使用 Δtau314 水平的测量，这是一个特定的。治疗和临床相关的生物标志物，作为我们测试漏斗的一部分，用于衡量我们探针的功效我们的探针设计和开发将采用三个并行的化合物表征路径和方法。优化，其中每一项都会告知另一项关于影响特异性和效力的 caspase-2 结合。我们的三个目标是开发 (1) 由 caspase-2 特异性切割的蛋白质制成的探针，(2) 探针来自 HTS 后续产品，以及 (3) 来自已知选择性 caspase-2 抑制剂的探针，我们的目标是：产生对目标蛋白的体外效力 <100 nM 的探针或工具化合物，具有 >30 倍的能力相对于同一家族中序列相关目标的选择性，已根据“行业- 标准”的药理学相关脱靶组，并已在 <1 的细胞中证明了正靶效应 µM。为了证明体内相关性，我们将使用 Morris 水迷宫在 rTg4510 小鼠中测试这些探针，我们期望这些专门针对 caspase-2 的探针能够恢复一个完善的认知模型。最终，我们将使用这些特定的 caspase-2 来提高这些老年小鼠的认知能力。探针来研究与 caspase-2 活性有关的广泛神经系统疾病。这将构成重要的垂直进步并刺激治疗药物的发展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