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: 8360595
• 负责人: GREGORY RICHARD COOK
• 金额: $ 5.04万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360595
• 关键词: Active Sites; Binding; Biochemistry; Centers of Research Excellence; Chemotherapy-Oncologic Procedure; Chronic Disease; Clinical; Clinical Trials; Development; Disease; Drug Design; Drug Kinetics; Enzymes; Evaluation; Fingers; Funding; Future; Genes; Genetic Transcription; Goals; Grant; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Individual; Isoenzymes; Lysine; Methodology; Modeling; Molecular; National Center for Research Resources; Organic Synthesis; Peptide Hydrolases; Play; Principal Investigator; Proteins; Regulation; Research; Research Infrastructure; Resources; Role; Source; Specificity; Structure; Therapeutic; United States National Institutes of Health; Up-Regulation; Vorinostat; Zinc; Zolinza; base; chromatin remodeling; cost; design; enzyme model; inhibitor/antagonist; novel strategies; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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. A. Specific Aims Specific Aim 1: Design ixozyme-specific HDAC inhiitors with moderate potency for ideal therapeutic application using computational biochemistry methodologies. By selectively inhibiting individual HDAC isozymes, a better understanding of their role in disease states will be obtained. Currently the most promising HDAC inhibitors emerging from clincal trials have broad-spectrum activity and could pose future clinical issues. Key to this specific aim is the development of competent models for DHAC class I proteins based upon the crystal structure of HDAC8. Highly potent HDACi's have not been beneficial in clinical trials due to upregulation of many genes. We hypotehsize compounds with moderate potency, simliar to SAHA, and with isozyme specificity will be advantageous. Specific Aim 2: Synthesize and evaluate isozyme-specific HDAC inhibitors. A two-pronged approach will be undertaken. First, compounds with hydrophobic fingers to bind deeper in the active site of HDACs will be made based on already obtained preliminary results. Simultaneously, as new models are refinded, HDACi's will be designed to interact specifically with individual isozymes.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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。 A.具体目标 具体目标1：使用计算生物化学方法设计具有中等效力的ixozyme特异性HDAC抑制剂，用于理想的治疗应用。通过选择性抑制个体HDAC同工酶，将获得对它们在疾病状态中的作用的更好理解。目前，临床试验中最有前途的HDAC抑制剂具有广谱活性，可能会带来未来的临床问题。这一特定目标的关键是基于HDAC 8的晶体结构开发DHAC I类蛋白的胜任模型。由于许多基因的上调，高效HDACi在临床试验中没有益处。我们推测具有中等效力、类似于SAHA且具有同工酶特异性的化合物将是有利的。 具体目标2：合成和评价同工酶特异性HDAC抑制剂。将采取双管齐下的办法。首先，基于已经获得的初步结果，将制备具有疏水指状物的化合物以更深地结合HDAC的活性位点。同时，随着新模型的改进，HDACi将被设计成与单个同工酶特异性相互作用。