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Title: Reversible and irreversible LSD1 inhibitors
Author: Borrello, Maria Teresa
ISNI:       0000 0004 5923 2332
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2016
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Environmental factors and lifestyle can alter the way our genes are expressed influencing a network of chemical switches within our cells collectively known as the Epigenome. Among the epigenetic mechanisms orchestrating the gene expression, methylation is of foremost importance and probably fair to say, still incompletely decoded. Dysregulations of histone methylation patterns lead to the repression or activation of signalling pathways that often promote the genesis and progression of disease states. Lysine specific demethylase 1 (LSD1) oxidatively removes methyl groups from histone H3 and its aberrant activity has been correlated with the development of a broad range of pathologies. Therefore, specific inhibitors of LSD1 have potential in pharmacological applications. Research into LSD1 and its functions in normal and abnormal cells has been hindered by the lack of a specific and potent suppressor. The development of a selective inhibitor could not only foster the understanding of the biological roles of LSD1 but also represent a breakthrough for the design of novel drugs for a range of burdensome diseases. Here we investigate on reversible and irreversible inhibitors of LSD1, with the hope of broadening the current knowledge on this epigenetic target. By analysing the LSD1 interaction with the transcription factor Snail-1, we generated a series of small peptides as potential reversible inhibitors. The synthetic peptides were then evaluated in cellular assays. In search of novel non-covalent LSD1 blockers, we next explored Phage Display technology. Thereafter, we targeted LSD1 covalently by synthesising multiple structural analogues of the clinically used antidepressant TCP (ParnateĀ®), which is a known irreversible suppressor of LSD1 activity. We evaluated their ability of inhibiting LSD1 in a cell-free assay and the compounds showing enzymatic inhibition were tested as potential anti-proliferative and differentiating agents in leukaemia cell lines. Finally, we generated activity-based probes to fluorescently label LSD1 for biological applications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available