Imaging Histone Decatelylase (HDAC) Inhibition in Cancer

癌症中组蛋白癸酰酶 (HDAC) 抑制的成像

• 批准号: 8566733
• 负责人: Ralph Mazitschek
• 金额: $ 72.22万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8566733
• 关键词: Address; Behavior; Binding; Biochemistry; Biological; Biological Process; Biology; Biomedical Research; Boron; Cancer Center; Cathepsins; Chemicals; Chromatin; Clinical Trials; Cutaneous; Development; Drug or chemical Tissue Distribution; Dyes; Enzymes; Epigenetic Process; Fluorine; Fluorochrome; Gene Expression; Gene Expression Regulation; Generic Drugs; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Image; Libraries; Ligands; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of ovary; Metalloproteases; Methods; Molecular Biology; Organ; Pathogenesis; Peptides; Positron-Emission Tomography; Pre-Clinical Model; Protein Acetylation; Regulation; Reporting; Research; Research Personnel; Seasons; Stromal Cells; T-Cell Lymphoma; Tail; Testing; Tissues; Transcription Regulatory Protein; Treatment Efficacy; Vorinostat; Work; Zolinza; base; cancer cell; cancer therapy; design; enzyme activity; enzyme substrate; in vivo; interest; molecular imaging; mouse model; novel; screening; small molecule; therapeutic target

The overall goal of this project is to develop novel compounds and approaches to image histone decatelylases (HDACs), key enzymes associated with epigenetic gene regulation. HDACs have been linked to the pathogenesis of cancer, and small-molecule HDAC inhibitors (HDACi) have been shown to have significant biological effects in preclinical models of cancer as well as in early clinical trials. Our group has recently developed class-specific and pan-HDACi based on rational ligand and substrate design, HDAC biochemistry, and on high-content screening (Nat Chem Biol 2009;6:238-243). Based on these developments, we will now address fundamental questions regarding HDAC biology and inhibition, such as: 1) What are the tissue distribution levels of HDACs in vivo? 2) Do cancer cells have different expression levels to stromal cells? 3) What are the activity levels of HDACs (not just abundance) in vivo? 4) What are HDAC activity levels at the whole organ level? 5) Can HDAC inhibition (using HDACi) be quantitated using imaging? The central hypothesis underlying this research is that novel imaging agents will allow us to both visualize the distribution of HDACs as well as quantitate their activity levels in vivo. The specific aims are thus: 1) to develop and test small molecule HDAC ligands for imaging; 2) to validate and test imaging agents in mouse models; and 3) to image HDAC expression and therapeutic efficacy of HDAC inhibition in ovarian cancer in vivo.

该项目的总体目标是开发新颖的化合物和图像组蛋白的方法 与表观遗传基因调节相关的固定酶（HDACS），关键酶。 HDAC一直是 与癌症的发病机理和小分子HDAC抑制剂（HDACI）有关 在癌症的临床前模型以及早期临床试验中具有显着的生物学作用。我们的 Group最近基于理性配体和底物开发了类特异性和PAN-HDACI 设计，HDAC生物化学和高含量筛选（Nat Chem Biol 2009; 6：238-243）。基于 这些发展，我们现在将解决有关HDAC生物学和抑制的基本问题， 例如：1）体内HDAC的组织分布水平是多少？ 2）癌细胞有不同的 基质细胞的表达水平？ 3）体内HDAC的活性水平（不仅仅是丰度）？ 4）整个器官水平的HDAC活性水平是多少？ 5）可以抑制HDAC（使用HDACI） 使用成像定量？这项研究的基本假设是新型成像剂 将使我们既可以看到HDAC的分布，又可以在体内定量其活性水平。 因此，具体目的是：1）开发和测试小分子HDAC配体进行成像； 2）验证 并在小鼠模型中测试成像剂； 3）图像HDAC表达和治疗功效 体内卵巢癌的HDAC抑制作用。