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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：
Damian Winston Young
金额：
$ 42.95万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
https://reporter.nih.gov/project-details/10624458
关键词：
Acceleration Amino Acids Area Bar Codes Basic Science Binding Biochemical Pathway Biological Catalogs Cell Line Cells Chemicals Chromatin Clinical Collection Data Analyses Defect Detection Development Disease Drug Design Drug Targeting Elements Enzymes Frustration Generations Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Isotopes Libraries Life Ligation Malignant Neoplasms Mass Spectrum Analysis Measures Metabolic Methodology Methods Molecular Mechanisms of Action Neutrons Nuclear Pattern Pharmaceutical Preparations Pharmacology Photoaffinity Labels Physiological Piperazines Process Proteins Proteome Reaction Reagent Regulation Resistance Resolution Sampling Site Specificity Statistical Data Interpretation Structure Support Groups System Systems Analysis Technology Testing Toxic effect Treatment Efficacy Work blind candidate selection clinical application combinatorial design drug candidate drug development drug discovery drug-like compound enantiomer high throughput screening in vivo inhibitor innovation novel novel drug class pharmacologic scaffold side effect small molecule small molecule inhibitor success

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：
Current protocols
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：
Biochemical Society transactions
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：
Molecular therapy : the journal of the American Society of Gene Therapy
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：
Molecules (Basel, Switzerland)
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：
ACS MEDICINAL CHEMISTRY LETTERS
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.