eprintid: 1500853
rev_number: 25
eprint_status: archive
userid: 608
dir: disk0/01/50/08/53
datestamp: 2016-10-13 10:38:30
lastmod: 2019-08-11 09:32:45
status_changed: 2016-10-13 10:38:30
type: thesis
metadata_visibility: show
creators_name: Bellany, F
title: Development of Aurora A Kinase-Specific Inhibitors as Anticancer Agents
ispublished: unpub
divisions: A01
divisions: B04
divisions: C06
divisions: F56
abstract: It is believed that one in two people will be diagnosed with cancer during their lifetime. Therefore,
there is an urgent need to research and develop new treatments and one of the recent areas of cancer
research has targeted components of mitosis, mainly the mitotic kinases. This research project has
focused on the Aurora kinases, a family of serine/threonine kinases which play a central role in
chromosome segregation and cell division during mitosis.
It has recently been demonstrated that Coenzyme A (CoA) is a highly selective ATP-competitive
inhibitor of Aurora A kinase. However, the pharmacokinetic properties of CoA, in particular its poor
cell permeability, need improvement. The aim of this PhD is to design and synthesise analogues of CoA
that are more “drug-like”, whilst conserving the features that lead to the selective inhibition.
Three series of compounds have been synthesised during the course of this research. The first,
conserved the pantothenamide tail and focused on replacing the adenosine moiety of CoA with a
heteroaromatic head group based around VX680 – a known inhibitor of the Aurora kinases. During the
synthesis of this series, a problematic key step was optimised using a Design of Experiment (DoE)
approach. The second series focused on replacing the pyrophosphate group of CoA with known
literature mimics to improve the overall drug likeness of the compound before starting to investigate
the structure activity relationship (SAR) around the tail region of CoA. The final series of compounds
were synthesised to investigate the possible location of the pantetheine tail within the Aurora A binding
site – believed to be important for selectivity towards Aurora A. These analogues conserved the
structure of CoA and attached affinity labels to the terminal –SH with the capability of covalently
interacting with residues within the active site of the kinase.
date: 2016-06-28
date_type: published
oa_status: green
full_text_type: other
thesis_class: doctoral_open
language: eng
thesis_view: UCL_Thesis
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1136527
lyricists_name: Bellany, Fiona
lyricists_id: BELLA85
actors_name: Bellany, Fiona
actors_id: BELLA85
actors_role: owner
full_text_status: public
pages: 294
event_title: University College London
institution: UCL (University College London)
department: Chemistry
thesis_type: Doctoral
citation:        Bellany, F;      (2016)    Development of Aurora A Kinase-Specific Inhibitors as Anticancer Agents.                   Doctoral thesis , UCL (University College London).     Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1500853/1/Fiona%20Bellany%20-%20PhD%20Thesis.pdf