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

• 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
• 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

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.

项目摘要 溴结构域蛋白充当表观遗传“读取器”，并在基因表观遗传调节中起关键作用 通过与组蛋白尾部上的乙酰化赖氨酸残基（AC-K）结合来转录。 BET蛋白具有两个保守的 N末端溴结构域（BD1和BD2）。溴结构域和末端结构域（BET）抑制剂具有 在过去的几年中，是肿瘤治疗的广泛研究。最近，据报道抑制剂 在学习和记忆之类的脑功能中发挥关键作用，还显示了底物的治疗潜力 虐待。 BET蛋白质在确定组织特异性转录程序中具有不同的作用 特定的BET领域对于研究潜在治疗的安全至关重要。 不幸的是，没有合适的非侵入性成像工具来研究BET表达和活动 动物或人类。在体内可视化特定BET域的技术的开发代表了一个关键 了解大脑中BET的正常功能和病理生理学的步骤。而且，这些技术 将加速与特定BET相互作用的小分子疗法的发现 域。该项目旨在为BET的BD2域开发新颖的PET成像问题。我们将修改 我们的铅化合物的结构和用氟-18的标记抑制剂的结构，并评估了这些抑制剂的潜力 通过成像分布和药代动力学，可以用作人类下注的F-18放射性分子 在啮齿动物和非人类隐私中。

项目成果

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
• 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