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.
Organisations
People |
ORCID iD |
| A Ganesan (Primary Supervisor) | |
| Adam Lee (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011216/1 | 01/10/2015 | 31/03/2024 | |||
| 1799707 | Studentship | BB/M011216/1 | 01/10/2016 | 30/09/2020 | Adam Lee |
| Description | We developed a series of novel LSD1 inhibitors based on a clinical candidate developed by GlaxoSmithKline, GSK2879552. Our inhibitors have been shown to be active against LSD1 in preliminary inhibition assays and shown to be effective in anti-proliferation assays in cancer cells. in additon, we synthesised a dual inhibitor of both LSD1 and the zinc dependent HDACs. A number of biological tests have been, and continue to be, carried out by collaborators which suggest that our inhibitor is effective. Also, we developed a series of novel, potental HDAC6 inhibitors which now require biological testing. Finally, we synthesised a series of potental zinc dependent HDAC inhibitors with a carboxylic acid war head which also now require biological testing. |
| Exploitation Route | Compounds could be further optimised and further biological testing carried out. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |