%0 Thesis
%9 Doctoral
%A Bellany, F
%B Chemistry
%D 2016
%F discovery:1500853
%I UCL (University College London)
%P 294
%T Development of Aurora A Kinase-Specific Inhibitors as Anticancer Agents
%U https://discovery.ucl.ac.uk/id/eprint/1500853/
%X 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.