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 溴结构域蛋白作为表观遗传“阅读器”，在基因的表观遗传调控中起关键作用， 通过结合组蛋白尾部的乙酰化赖氨酸残基（Ac-K）进行转录。BET蛋白具有两个保守的 N-末端溴结构域（BD 1和BD 2）。布罗莫结构域和末端外结构域（BET）抑制剂具有 在过去的几年里，它被广泛研究用于肿瘤治疗。最近，已经报道了BET抑制剂 在大脑功能中发挥关键作用，如学习和记忆，也显示出治疗潜力的物质 虐待BET蛋白在调节组织特异性转录程序中具有不同的作用，因此，靶向 特定BET结构域的确定对于研究潜在治疗剂的安全性将是重要的。 不幸的是，没有合适的非侵入性成像工具来研究BET表达和活性， 用于在体内可视化特定BET结构域的技术的发展代表了一个关键， 进一步了解脑内BET的正常功能和病理生理学。此外，这些技术 将加速发现选择性地与特定BET相互作用的小分子治疗剂 域.该项目旨在开发BET BD 2结构域的新型PET成像探针。我们将修改 我们的先导化合物的结构和标记的BET抑制剂与氟-18和评估的潜力，这些 分子作为人体内BET的F-18放射性示踪剂，通过成像其分布和药代动力学 在啮齿类动物和非人类灵长类动物中。

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