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

点击翻译按钮获取中文摘要

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.