COBRE: NDSU: PROJECT 2: DESIGN, SYNTHESIS AND EVALUATION OF ISOZYME-SPECIFIC

COBRE：NDSU：项目 2：同工酶特异性的设计、合成和评估

• 批准号: 8167862
• 负责人: GREGORY RICHARD COOK
• 金额: $ 5.09万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167862
• 关键词: Biochemistry; Chemotherapy-Oncologic Procedure; Chronic Disease; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Drug Design; Drug Kinetics; Enzymes; Evaluation; Funding; Genetic Transcription; Goals; Grant; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Institution; Isoenzymes; Lysine; Modeling; Molecular; Organic Synthesis; Play; Regulation; Research; Research Personnel; Resources; Role; Source; Specificity; United States National Institutes of Health; Vorinostat; Zinc; Zolinza; base; chromatin remodeling; design; enzyme model; novel strategies; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Histone deacetylases (HDACs) are zinc-dependent hydrolytic enzymes involved in chromatin remodeling and play a critical role in the regulation of gene transcription via deacetylation of histone lysine residues. The small molecule HDAC inhibitor (HDI), suberoylanilide hydroxamic acid (SAHA; also known as Zolinza or Vorinostat) is currently in many clinical trials for cancer chemotherapy and holds great promise for the amelioration of other diseases as well. However, SAHA and other HDIs in development have molecular functionality and broad-spectrum activity with known pharmacokinetic difficulties and will certainly be problematic in the treatment of chronic illnesses. This research will develop new classes of HDIs and offer novel strategies for HDAC inhibition. Key to this project is the design of isozyme-specific HDIs based on competent models of the enzyme. Missing from current efforts in the development of HDIs is the availability of good models of the HDAC Class I isozymes from which to base drug design. This project combines both computational biochemistry and organic synthesis to achieve the goal of isozyme specificity in an HDI.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 组蛋白脱乙酰酶（HDAC）是一种锌依赖性的染色质水解酶 重塑，并通过去乙酰化的基因转录调控中发挥关键作用， 组蛋白赖氨酸残基。小分子HDAC抑制剂（HDI）辛二酰苯胺异羟肟酸 SAHA（也称为Zolinza或Vorinostat）目前正在进行许多癌症临床试验 化疗，并持有很大的希望，为改善其他疾病以及。然而，SAHA和其他正在开发的HDIs具有分子功能性和广谱活性，具有已知的药代动力学困难，在治疗慢性疾病方面肯定会有问题。 这项研究将开发新的HDIs类别，并为HDAC抑制提供新的策略。该项目的关键是基于酶的主管模型设计同工酶特异性HDIs。在HDIs的开发中，目前的努力中缺少的是HDAC I类同工酶的良好模型的可用性，以基于该模型进行药物设计。这个项目结合了计算生物化学和有机合成，以实现HDI中同工酶特异性的目标。