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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 组蛋白脱乙酰酶(HDAC)是参与染色质的锌依赖水解酶 通过去乙酰化在基因转录调控中起关键作用 组蛋白赖氨酸残基。小分子HDAC抑制剂(HDI)--异羟基苯乙酰亚胺 ACID(SAHA；也被称为佐林扎或Vorinostat)目前正在进行许多癌症临床试验 化疗也为其他疾病的改善带来了巨大的希望。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，在治疗慢性病方面肯定会出现问题。 这项研究将开发新的HDI类药物，并为抑制HDAC提供新的策略。这个项目的关键是基于酶的胜任模型设计特定于同工酶的HDI。目前开发人类发展指数的努力中，缺少用于基础药物设计的HDAC I类同工酶的良好模型的可用性。该项目结合了计算生物化学和有机合成，以实现HDI同工酶专一性的目标。

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.