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

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 组蛋白脱乙酰酶 (HDAC) 是参与染色质的锌依赖性水解酶 重塑并通过脱乙酰化在基因转录调节中发挥关键作用 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 酸（SAHA；也称为 Zolinza 或 Vorinostat）目前正在进行许多癌症临床试验 化疗对改善其他疾病也有很大的希望。然而，SAHA 和其他正在开发的 HDI 具有分子功能和广谱活性，具有已知的药代动力学困难，并且在慢性疾病的治疗中肯定会存在问题。 这项研究将开发新类别的 HDIs 并提供新的 HDAC 抑制策略。该项目的关键是基于酶的有效模型设计同工酶特异性 HDI。当前 HDIs 开发工作中缺少的是可用于基础药物设计的 HDAC I 类同工酶的良好模型。该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。

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.