Neutron encoded activity based probes
基于中子编码活动的探针
基本信息
- 批准号:10624458
- 负责人:
- 金额:$ 42.95万
- 依托单位:
- 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:2020-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAmino AcidsAreaBar CodesBasic ScienceBindingBiochemical PathwayBiologicalCatalogsCell LineCellsChemicalsChromatinClinicalCollectionData AnalysesDefectDetectionDevelopmentDiseaseDrug DesignDrug TargetingElementsEnzymesFrustrationGenerationsHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorIsotopesLibrariesLifeLigationMalignant NeoplasmsMass Spectrum AnalysisMeasuresMetabolicMethodologyMethodsMolecular Mechanisms of ActionNeutronsNuclearPatternPharmaceutical PreparationsPharmacologyPhotoaffinity LabelsPhysiologicalPiperazinesProcessProteinsProteomeReactionReagentRegulationResistanceResolutionSamplingSiteSpecificityStatistical Data InterpretationStructureSupport GroupsSystemSystems AnalysisTechnologyTestingToxic effectTreatment EfficacyWorkblindcandidate selectionclinical applicationcombinatorialdesigndrug candidatedrug developmentdrug discoverydrug-like compoundenantiomerhigh throughput screeningin vivoinhibitorinnovationnovelnovel drug classpharmacologicscaffoldside effectsmall moleculesmall molecule inhibitorsuccess
项目摘要
Drugs are designed to modulate the function of a critical protein involved in a disease; however, almost all small
molecules have off-targets which can mitigate or altogether terminate their therapeutic efficacy. Unfortunately,
there are no general methods that can identify all the protein targets that a drug binds to in an unbiased manner.
For example, Histone Deacetylase Inhibitors (HDACIs) show promising clinical activity in many diseases;
however, they are generally of low to moderate specificity and may act in part through, or be hindered by,
uncharacterized off-target interactions. We propose a strategy that will allow for rapid and deep
pharmacological profiling of early drug candidates that 1) identifies protein targets with extraordinary
confidence, 2) localizes the precise site of interaction often with amino acid residue specificity, 3) is robust against
metabolic alterations, 4) distinguishes the pharmacology of metabolites, 5) quantitates differences in
pharmacological activity between cellular contexts. With this approach we will quantitate all interactions that
each inhibitor has with proteins in a living cell. An neutron-encoded ‘bar code’ is added to activity-based
probes during a click capture and release that allows us to blindly trace the drug in a nominal mass independent
manner and simultaneously introduce quantitation channels. The barcodes are revealed in the isotopic fine
structure by high resolution mass spectrometry yet do not compromise sensitivity at lower resolution
fragmentation spectra. The neutron bar code is implemented by moving neutrons between elements and results
in a prescribed pattern of relativistic nuclear mass defects embedded in the framework of a small molecule. With
this method we can confidently retrieve drug-protein reaction products from in vivo systems regardless of
metabolic alterations to the HDAC inhibitors, measure a pharmacological profile and determine molecular
mechanism of action. Our central hypothesis is that neutron encoded activity based probe pharmacological
profiling combined with innovative fragment-based discovery to generate selective HDACIs will enable the
generation of a library of highly characterized and diversely selective HDACI probes. This will be realized through
three specific aims: in aim 1 we will employ a novel and systematically diverse group of sp3-enriched fragments
to generate HDACIs that sample the rim region of HDACs leading to highly selective interactions. In aim 2 we
will measure the pharmacological profile of our novel HDACi’s and their effect on histone acetylation. In aim 3,
we will develop a multiplexed barcoding system which to enable higher detection and resolution of drug targets
over the entire proteome. This overcomes many challenges universal to early stage drug development
efforts that have frustrated the development of specific HDAC inhibitors in particular. Although HDACIs
will be the general focus of this proposal our method is general for drug development in any area.
药物被设计用于调节与疾病有关的关键蛋白质的功能;然而,几乎所有的小分子药物都是通过调节蛋白质的功能来实现的。
分子具有脱靶,这可以减轻或完全终止它们的治疗功效。不幸的是,
没有通用的方法可以以无偏的方式鉴定药物结合的所有蛋白质靶。
例如,组蛋白去乙酰化酶抑制剂(HDACIs)在许多疾病中显示出有希望的临床活性;
然而,它们通常具有低至中等特异性,
未表征的脱靶相互作用。我们提出了一个战略,将允许快速和深入的
早期候选药物的药理学特征分析,1)鉴定具有显著
置信度,2)定位相互作用的精确位点,通常具有氨基酸残基特异性,3)对
代谢改变,4)区分代谢物的药理学,5)定量
细胞环境之间的药理活性。通过这种方法,我们将量化所有的相互作用,
每种抑制剂都与活细胞中的蛋白质发生作用。一个中子编码的“条形码”被添加到基于活动的
探针在点击捕获和释放,使我们能够盲目地跟踪药物在一个标称质量独立
方式,同时引入定量通道。条形码显示在同位素微粒中
但在较低分辨率下不损害灵敏度
碎裂谱中子条形码是通过在元素和结果之间移动中子来实现的
在小分子框架中嵌入相对论性核质量缺陷的规定模式中。与
这种方法我们可以自信地从体内系统中回收药物-蛋白质反应产物,
HDAC抑制剂的代谢改变,测量药理学特征并确定分子水平。
作用机制。我们的中心假设是基于中子编码活性的探针药理学
分析与创新的基于片段的发现相结合,以生成选择性HDACI,
产生高度表征的和双特异性选择性HDACI探针文库。这将通过以下方式实现
三个具体目标:在目标1中,我们将采用一组新的和系统多样的富含sp3的片段
以产生HDACIs,所述HDACIs对HDACs的边缘区域进行采样,从而导致高度选择性的相互作用。在目标2中,
将测量我们的新型HDACi的药理学特征及其对组蛋白乙酰化的影响。在目标3中,
我们将开发一种多重条形码系统,以实现更高的药物靶点检测和分辨率,
覆盖整个蛋白质组。这克服了早期药物开发普遍存在的许多挑战
这些努力尤其阻碍了特定HDAC抑制剂的开发。虽然HDACIs
将是本提案的总体重点,我们的方法适用于任何领域的药物开发。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Expeditious Extraction of Histones from Limited Cells or Tissue Samples and Quantitative Top-Down Proteomic Analysis.
- DOI:10.1002/cpz1.26
- 发表时间:2021-03
- 期刊:
- 影响因子:0
- 作者:Holt MV;Wang T;Young NL
- 通讯作者:Young NL
Mechanistic insights into KDM4A driven genomic instability.
- DOI:10.1042/bst20191219
- 发表时间:2021-02-26
- 期刊:
- 影响因子:3.9
- 作者:Young NL;Dere R
- 通讯作者:Dere R
Gene therapy using Aβ variants for amyloid reduction.
使用 Aβ 变体进行淀粉样蛋白减少的基因治疗。
- DOI:10.1016/j.ymthe.2021.02.026
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Park,Kyung-Won;Wood,CalebA;Li,Jun;Taylor,BethanyC;Oh,SaeWoong;Young,NicolasL;Jankowsky,JoannaL
- 通讯作者:Jankowsky,JoannaL
A Concise Synthetic Method for Constructing 3-Substituted Piperazine-2-Acetic Acid Esters from 1,2-Diamines.
- DOI:10.3390/molecules27113419
- 发表时间:2022-05-25
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Chemical Catalysis Guides Structural Identification for the Major In Vivo Metabolite of the BET Inhibitor JQ1.
- DOI:10.1021/acsmedchemlett.3c00464
- 发表时间:2024-01-11
- 期刊:
- 影响因子:4.2
- 作者:Holmes, Secondra;Jain, Prashi;Rodriguez, Kenneth Guzman;Williams, Jade;Yu, Zhifeng;Cerda-Smith, Christian;Samuel, Errol L. G.;Campbell, James;Hakenjos, John Michael;Monsivais, Diana;Li, Feng;Chamakuri, Srinivas;Matzuk, Martin M.;Santini, Conrad;Mackenzie, Kevin R.;Young, Damian W.
- 通讯作者:Young, Damian W.
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Damian Winston Young其他文献
Damian Winston Young的其他文献
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{{ truncateString('Damian Winston Young', 18)}}的其他基金
DNA-Encoded Chemistry Technology (DEC-Tec) Core
DNA 编码化学技术 (DEC-Tec) 核心
- 批准号:
10164825 - 财政年份:2017
- 资助金额:
$ 42.95万 - 项目类别:
Coordinating CMLD methodology with the build/couple/pair strategy to yield comple
将 CMLD 方法与构建/耦合/配对策略相协调,以生成完整的
- 批准号:
7696753 - 财政年份:2008
- 资助金额:
$ 42.95万 - 项目类别:
Coordinating CMLD methodology with the build/couple/pair strategy to yield comple
将 CMLD 方法与构建/耦合/配对策略相协调,以生成完整的
- 批准号:
7897836 - 财政年份:
- 资助金额:
$ 42.95万 - 项目类别:
Coordinating CMLD methodology with the build/couple/pair strategy to yield comple
将 CMLD 方法与构建/耦合/配对策略相协调,以生成完整的
- 批准号:
7932232 - 财政年份:
- 资助金额:
$ 42.95万 - 项目类别:
Discovery of UHRF1 inhibitors in the treatment of hepatocellular carcinoma
UHRF1抑制剂治疗肝细胞癌的发现
- 批准号:
9789211 - 财政年份:
- 资助金额:
$ 42.95万 - 项目类别:
Coordinating CMLD methodology with the build/couple/pair strategy to yield comple
将 CMLD 方法与构建/耦合/配对策略相协调,以生成完整的
- 批准号:
8144393 - 财政年份:
- 资助金额:
$ 42.95万 - 项目类别:
Discovery of UHRF1 inhibitors in the treatment of hepatocellular carcinoma
UHRF1抑制剂治疗肝细胞癌的发现
- 批准号:
9789847 - 财政年份:
- 资助金额:
$ 42.95万 - 项目类别:
Discovery of UHRF1 inhibitors in the treatment of hepatocellular carcinoma
UHRF1抑制剂治疗肝细胞癌的发现
- 批准号:
9635376 - 财政年份:
- 资助金额:
$ 42.95万 - 项目类别:
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