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Selective PET imaging probes targeting BD1 of N-terminal bromodomains

靶向 N 端溴结构域 BD1 的选择性 PET 成像探针

基本信息

批准号：
10054837
负责人：
Changning Wang
金额：
$ 24.93万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2020-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054837
关键词：
Aging Animals Binding Biological Assay Brain Bromodomain Cellular biology Chromatin Clinical Trials Coin DNA Sequence Data Development Differentiation and Growth Disease Dose Drug Addiction Drug Kinetics Drug Targeting Drug abuse Enzymes Epigenetic Process FDA approved Fluorine Functional disorder General Hospitals Genetic Transcription Genome Goals Grant Growth and Development function Health Histones Human Image Imaging Device Imaging Techniques Inflammation Investigative Techniques Label Lead Learning Lysine Massachusetts Measurement Memory Metabolism Methods Modification N-terminal Nature Oncology Patient Selection Pharmaceutical Preparations Pharmacology Pharmacotherapy Plasma Play Positron-Emission Tomography Process Protein Family Radiolabeled Reader Regulation Reporting Research Resources Rodent Role Safety Scientist Structure Substance abuse problem Tail Techniques Tertiary Protein Structure Therapeutic Therapeutic Trials Time Tissues Tracer Validation base bioimaging density design epigenetic regulation human imaging imaging probe in vivo in vivo imaging inhibitor/antagonist interest kinetic model man molecular imaging neural circuit non-invasive imaging nonhuman primate novel novel therapeutics prevent programs protein function radiochemical radiotracer response small molecule therapeutics technique development tool tool development tumor

项目摘要

Project Summary Bromodomain proteins function as epigenetic “readers” and play a key role in epigenetic regulation of gene transcription by binding to acetylated lysine residues (Ac-K) on histone tails. BET proteins have two conserved N-terminal bromodomains (BD1 and BD2). The bromodomain and extra-terminal domain (BET) inhibitors have been extensive studied for tumors treatment in the past few years. Recently, BET inhibitors have been reported to play a key role in brain functions, such as learning and memory, also show a therapeutic potential for substance abuse. BET proteins have diverse roles in regulating tissue-specific transcriptional programs, therefore, targeting of specific BET domains will be important for investigating the safety of potential therapeutics. Unfortunately, there are no suitable non-invasive imaging tools for investigating BET expression and activity in animals or in man. The development of techniques for visualizing specific BET domains in vivo represents a key step in understanding both the normal function and pathophysiology of BET in brain. Moreover, these techniques will accelerate the discovery of small molecule therapeutics that selectively interacts with the specific BET domains. The project is designed to develop novel PET imaging probes for BD2 domain of BET. We will modify the structure of our lead compounds and label BET inhibitors with fluorine-18 and evaluate the potential of these molecules to serve as F-18 radiotracers for BET in humans by imaging their distribution and pharmacokinetics in rodents and non-human primates.

项目总结

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models.

DOI：
10.1016/j.jbc.2022.101794
发表时间：
2022-04
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Zhang S;Bai P;Lei D;Liang Y;Zhen S;Bakiasi G;Pang H;Choi SH;Wang C;Tanzi RE;Zhang C
通讯作者：
Zhang C

A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain.

DOI：
10.1039/d2cc03785h
发表时间：
2022-08-25
期刊：
CHEMICAL COMMUNICATIONS
影响因子：
4.9
作者：
Bai, Ping;Yan, Liu;Bagdasarian, Frederick A.;Wilks, Moses Q.;Wey, Hsiao-Ying;Wang, Changning
通讯作者：
Wang, Changning