Inhibition and biochemical studies of cancer-relevant 2-oxoglutarate oxygenase AspH

癌症相关 2-酮戊二酸加氧酶 AspH 的抑制和生化研究

• 批准号: 2285026
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2285026
• 关键词: Inhibition; biochemical; studies; cancer; relevant

Aspartate/asparagine-beta-hydroxylase (AspH) is a 2-oxogluturate (2OG)-dependant oxygenase that catalyses the beta-hydroxylation of aspartate and asparagine residues in epidermal growth factor-like domains (EGFDs). AspH is highly overexpressed in several human cancer cell types, and its knockdown has been shown to limit tumour growth and metastatic spread. It is thought selective inhibition of AspH catalysis may be a successful mode of action for a novel, small-molecule anti-cancer therapeutic. This project will focus on the design of efficient AspH inhibitors, in particular those that target the substrate-binding pocket, as this should result in selectivity over related 2OG-dependent oxygenases. Two additional side projects involve the synthesis of a fluorescent AspH probe leading to the development of an affinity-based fluorescence polarization assay, and the preparation of diselenide bond-containing EGFDs that will allow biochemical studies into AspH substrate selectivity.This project falls within the EPSRC "Chemical biology and biological chemistry" research area.

天冬氨酸/天冬酰胺-β-羟化酶 (AspH) 是一种 2-氧化谷氨酸 (2OG) 依赖性加氧酶，可催化表皮生长因子样结构域 (EGFD) 中天冬氨酸和天冬酰胺残基的 β-羟基化。 AspH 在几种人类癌细胞类型中高度过度表达，其敲低已被证明可以限制肿瘤生长和转移扩散。人们认为，选择性抑制 AspH 催化可能是新型小分子抗癌治疗的成功作用模式。该项目将重点关注有效 AspH 抑制剂的设计，特别是那些针对底物结合袋的抑制剂，因为这应该会导致对相关 2OG 依赖性加氧酶的选择性。另外两个附带项目涉及荧光 AspH 探针的合成，从而开发基于亲和力的荧光偏振测定法，以及含有二硒键的 EGFD 的制备，这将允许对 AspH 底物选择性进行生化研究。该项目属于 EPSRC “化学生物学与生物化学”研究领域。