Caspase-2 Probe Compounds
Caspase-2 探针化合物
基本信息
- 批准号:10532777
- 负责人:
- 金额:$ 70.96万
- 依托单位:
- 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:
- 关键词:AMPA ReceptorsAccelerationAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAnimal ModelBindingBiological AssayBiological MarkersBiological ModelsBiologyBrainCASP2 geneCaspaseCellsChemicalsCognitionCognitiveCognitive deficitsCollectionCommunitiesCrystallographyCytoskeletal ProteinsDendritic SpinesDevelopmentDockingFamilyFrontotemporal DementiaFunctional disorderGlaucomaGoalsHealthHumanHuntington DiseaseHuntington geneImpaired cognitionIn VitroIndustry StandardMeasurementMeasuresMediatingModelingModificationMolecularMusNational Center for Advancing Translational SciencesNerve DegenerationNeuroblastomaNeurodegenerative DisordersNeurologicNeuronsOxidative StressParkinson DiseasePeptide HydrolasesPharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePostsynaptic MembraneProteinsProteolysisResearchResearch PersonnelRoleScientistSeriesSiteSpecificityStrokeStructure-Activity RelationshipSynapsesSynaptic TransmissionSynaptic plasticitySystemTauopathiesTestingTherapeuticTranslational ResearchUnited States National Institutes of HealthVisualizationWorkagedanalogclinically relevantcognitive functiondesigndisease phenotypedrug-like compoundexcitotoxicityfollow-upimprovedin vivoin vivo Modelinhibitorinnovationmetermorris water mazemultidisciplinarymutantnervous system disorderneurophysiologynovel therapeuticspharmacologicpostsynapticpreclinical studypreservationpreventreceptor functionrepairedside effectsmall moleculestructural biologysynaptic functiontau Proteinstherapeutic developmenttherapeutic targettooltransgene 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
半胱天冬酶-2与神经学适应症如中风、阿尔茨海默氏症、帕金森氏症和帕金森病有关。
亨廷顿病、神经母细胞瘤、神经眼科学和额颞叶痴呆。宽,长-
我们工作的长期目标是开发作为神经治疗剂的特异性半胱氨酸蛋白酶-2抑制剂。这
长期目标取决于首先开发caspase-2探针,使我们能够显示特定的
通过小分子探针药理学降低胱天蛋白酶-2活性导致疾病的改善
表型,最初在动物模型中。我们的具体目标都是针对caspase-2的发现和开发
但每个人都有不同的出发点。我们将使用测量314能级,
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,以衡量我们的探针的功效
在细胞中。我们的探针设计和开发将采用三种平行的化合物表征路径,
优化,其中每一个将告知另一个关于影响特异性和效力的半胱天冬酶-2结合。
我们的三个目标是:(1)从caspase-2特异性切割的蛋白质中开发探针,(2)探针
来自HTS后续,和(3)来自已知的选择性半胱天冬酶-2抑制剂的探针。我们的目标是
产生探针或工具化合物,其对靶蛋白具有<100 nM的体外效力,具有>30倍的
相对于同一家族中序列相关靶的选择性,已经针对“工业-
这是药理学相关脱靶的“标准”组,并且已经在<1
µM。为了证明体内相关性,我们将使用Morris水迷宫在rTg 4510小鼠中测试这些探针,
一个完善的认知模型。我们希望这些特异性靶向caspase-2的探针能够恢复
这些老年小鼠的认知能力没有明显的副作用。最终,我们将使用这些特定的caspase-2
探针,以调查广泛的神经系统疾病,其中半胱天冬酶-2活性已牵连。
这将构成一个重要的纵向进步,并刺激药物治疗的发展
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:
- 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:
- 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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Karen H Ashe其他文献
Natural oligomers of the amyloid-β protein specifically disrupt cognitive function
淀粉样β蛋白的天然低聚物特异性地破坏认知功能
- DOI:
10.1038/nn1372 - 发表时间:
2004-12-19 - 期刊:
- 影响因子:20.000
- 作者:
James P Cleary;Dominic M Walsh;Jacki J Hofmeister;Ganesh M Shankar;Michael A Kuskowski;Dennis J Selkoe;Karen H Ashe - 通讯作者:
Karen H Ashe
Karen H Ashe的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Karen H Ashe', 18)}}的其他基金
Prodrugs of potent and selective protease inhibitors as tauopathy therapeutics
作为 tau 蛋白病治疗剂的有效和选择性蛋白酶抑制剂的前药
- 批准号:
10761291 - 财政年份:2023
- 资助金额:
$ 70.96万 - 项目类别:
Molecular endophenotypes of H1 and H2 MAPT haplotypes
H1 和 H2 MAPT 单倍型的分子内表型
- 批准号:
9762819 - 财政年份:2018
- 资助金额:
$ 70.96万 - 项目类别:
Improved Transgenic Mouse Model of Alzheimer's Disease
改良的阿尔茨海默病转基因小鼠模型
- 批准号:
8244853 - 财政年份:2012
- 资助金额:
$ 70.96万 - 项目类别:
Improved Transgenic Mouse Model of Alzheimer's Disease
改良的阿尔茨海默病转基因小鼠模型
- 批准号:
8413428 - 财政年份:2012
- 资助金额:
$ 70.96万 - 项目类别:
相似海外基金
EXCESS: The role of excess topography and peak ground acceleration on earthquake-preconditioning of landslides
过量:过量地形和峰值地面加速度对滑坡地震预处理的作用
- 批准号:
NE/Y000080/1 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Research Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328975 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Continuing Grant
SHINE: Origin and Evolution of Compressible Fluctuations in the Solar Wind and Their Role in Solar Wind Heating and Acceleration
SHINE:太阳风可压缩脉动的起源和演化及其在太阳风加热和加速中的作用
- 批准号:
2400967 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Standard Grant
Market Entry Acceleration of the Murb Wind Turbine into Remote Telecoms Power
默布风力涡轮机加速进入远程电信电力市场
- 批准号:
10112700 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Collaborative R&D
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328973 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Continuing Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328972 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Continuing Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328974 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Continuing Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332916 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Standard Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332917 - 财政年份:2024
- 资助金额:
$ 70.96万 - 项目类别:
Standard Grant
Study of the Particle Acceleration and Transport in PWN through X-ray Spectro-polarimetry and GeV Gamma-ray Observtions
通过 X 射线光谱偏振法和 GeV 伽马射线观测研究 PWN 中的粒子加速和输运
- 批准号:
23H01186 - 财政年份:2023
- 资助金额:
$ 70.96万 - 项目类别:
Grant-in-Aid for Scientific Research (B)