Tran, TM;
(2017)
In-silico investigation of Coenzyme A selectivity for Aurora A kinase and development of an Aurora A kinase-selective inhibitor as a potential anticancer agent.
Doctoral thesis , UCL (University College London).
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Abstract
Centrosome amplification has been observed in most cancer cells, and is considered to be a “hallmark” of cancer cells. This process is commonly associated with chromosome segregation process in the mitosis phase in the cell cycle, which is tightly controlled by mitotic kinases. Among these kinases, the Aurora kinase family, Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), ensures the accurate progression of mitosis, including the formation of a bipolar mitotic spindle, accurate segregation of chromosomes and the completion of cytokinesis. AURKA has been seen to have the largest role in mitotic progression and checkpoint control pathways and overexpression of AURKA is most associated with cancer. Hence, interfering with AURKA activity has been considered to be a promising approach to anticancer agents. Professor Gout’s group has recently shown that Coenzyme A (CoA) selectively inhibits AURKA activity (IC50 of 4.4 μM). However, its large molecular weight (>500) and negatively charged phosphate group make it unsuitable as a drug candidate. This project was set to investigate the possible binding modes of CoA in the catalytic domain of AURKA. The corresponding interactions between CoA and protein residues would provide some insights in the selectivity of CoA towards AURKA. Furthermore, based on the understanding of the interactions between CoA and the catalytic domain of AURKA and the possible reasons behind the selectivity of CoA towards AURKA, in silico design and synthesis of a new highly selective and potent AURKA inhibitor based on the structure of CoA and current lead compounds which are in clinical trials for Aurora kinase inhibitors could be carried out.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | In-silico investigation of Coenzyme A selectivity for Aurora A kinase and development of an Aurora A kinase-selective inhibitor as a potential anticancer agent |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1530141 |
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