Targeting LSD1 from parasites to man

Lead Research Organisation: University of East Anglia
Department Name: Pharmacy

Abstract

Gene expression in all eukaryotic species is regulated by chemical modifications of DNA and histone proteins. One of the key processes involves the methylation of lysine residues in histones. Methylation is reversible as it is removed by demethylase enzymes such as lysine-specific demethylase (LSD1). In this project, you will design and synthesize novel reversible and irreversible inhibitors of LSD1 based on earlier work from our laboratory (Benelkebir et al., Bioorg. Med. Chem. 2011,19, 3709-3716; Tortorici et al., ACS Chem. Biol. 2013, 8, 1677-1682; Robertson et al., PLoS Comput. Biol. 2013, 9, e1003158). Our objective is to identify selective and cell-permeable inhibitors of LSD1 with high affinity (<1 uM) that can be used as molecular probes of LSD1 function. As part of the project, you will prepare affinity probes for LSD1 that are suitable for conjugation to fluorescent or affinity labels by alkyne-azide cycloaddition click chemistry. Once compounds are synthesized, you will biologically profile them for activity against cancer cells such as leukaemia as well as whole parasites responsible for neglected diseases such as Schistosoma and Trypanosoma. Promising compounds will be selected for further experiments and X-ray crystallization studies.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011216/1 01/10/2015 30/09/2023
1799707 Studentship BB/M011216/1 01/10/2016 30/09/2020 Adam Lee