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Development of Aurora A Kinase-Specific Inhibitors as Anticancer Agents

Bellany, F; (2016) Development of Aurora A Kinase-Specific Inhibitors as Anticancer Agents. Doctoral thesis , UCL (University College London).

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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.

Type: Thesis (Doctoral)
Title: Development of Aurora A Kinase-Specific Inhibitors as Anticancer Agents
Event: University College London
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1500853
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