Reversible and irreversible LSD1 inhibitors

Borrello, Maria Teresa (2016) Reversible and irreversible LSD1 inhibitors. Doctoral thesis, University of East Anglia.

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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
(Parnate®), 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.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Users 7376 not found.
Date Deposited: 07 Sep 2016 11:50
Last Modified: 07 Sep 2016 11:50


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