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Title: Development of ligands to target bromodomain-histone interactions
Author: Jennings, Laura Elizabeth
ISNI:       0000 0004 5359 2054
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Histone acetylation is an epigenetic post-translational modification recognised by the bromodomain, a protein module that forms part of multi-component complexes affecting transcription. This interaction plays fundamental cellular roles, and shows association with particular diseases including inflammation and cancer. The biological roles of bromodomains and the progress of ligands developed so far has been summarised in introductory Chapter 1. Work within the group has led to the development of a nanomolar ligand for BRD4, a BET bromodomain implicated in cancer and numerous diseases. Evaluation in an NCI-60 cancer cell screen indicated antiproliferative activity in a variety of cancer types. However, metabolic predictions indicate that this compound is unoptimised for use in vivo. Chapter 2 describes synthesis of a collection of analogues to improve the physical and pharmacokinetic properties of this series of compounds. This work identified compounds with equivalent affinity but greater predicted metabolic stability, as well as more potent derivatives. This research will direct the design of potent and metabolically stable derivatives that can be used in animal models. Chapter 3 describes work carried out towards the development of small molecules to target bromodomains for which there are no known ligands, using the FALZ bromodomain as an initial target. A fragment-based approach has identified a number of compounds that bind to different non-BET bromodomains. These fragments will be a useful starting point for the development of more potent and selective non-BET bromodomain ligands. As well as acetylated lysines, a number of other acylation post-translational modifications occur on lysine residues. Chapter 4 describes work carried out to investigate the interaction of other acylated lysine residues with bromodomains. This work highlighted that other acylated lysines can interact with bromodomains, and selectivity for particular bromodomains can also be achieved. These modified lysines could be incorporated into cognate peptides to improve in vitro peptide displacement assays, aiding the development of small molecular bromodomain probes.
Supervisor: Conway, Stuart; Humphreys, Philip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry ; bromodomains ; epigenetic probes ; epigenetics ; KAc ; acetyl lysine