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

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.
药物被设计用来调节与疾病有关的关键蛋白质的功能;然而,几乎都是小的

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.
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。
A Concise Synthetic Method for Constructing 3-Substituted Piperazine-2-Acetic Acid Esters from 1,2-Diamines.
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

Neutron encoded activity based probes
基于中子编码活动的探针
  • 批准号:
    10241549
  • 财政年份:
    2020
  • 资助金额:
    $ 42.95万
  • 项目类别:
Neutron encoded activity based probes
基于中子编码活动的探针
  • 批准号:
    10402917
  • 财政年份:
    2020
  • 资助金额:
    $ 42.95万
  • 项目类别:
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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