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

天冬氨酸/天冬氨酸- β -羟化酶（AspH）是一种2-氧葡萄糖（2OG）依赖的加氧酶，可催化表皮生长因子样结构域（EGFDs）中天冬氨酸和天冬氨酸残基的β -羟化。AspH在几种人类癌细胞类型中高度过表达，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的催化作用可能是一种新型的小分子抗癌药物的成功作用模式。该项目将专注于设计高效的AspH抑制剂，特别是针对底物结合袋的抑制剂，因为这将导致对相关的20g依赖性加氧酶的选择性。另外两个附带项目包括合成一种荧光AspH探针，从而开发一种基于亲和的荧光偏振测定方法，以及制备含二硒化物键的egfd，这将允许对AspH底物选择性进行生化研究。该项目属于EPSRC“化学生物学和生物化学”研究领域。

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.