Synthesis and evaluation of novel kinase inhibitors as anti-cancer agents

Kemp, TP 2012, Synthesis and evaluation of novel kinase inhibitors as anti-cancer agents , PhD thesis, University of Salford.

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Abstract

Disruption of protein kinase signalling pathways is often associated with cancer. The RhoA/ROCK kinase pathway has been shown to be constitutively expressed in many cancers and has also been shown to be involved in metastasis and apoptosis. ROCK is inhibited by the ATP mimic Y27632, which competitively binds the ATP binding site. All protein kinases possess an ATP binding pocket and subtle differences in these pockets can allow the development of highly selective ATP mimicking inhibitors. The major part of my research was to identify novel kinase inhibitor anti-cancer agents by synthesising ATP mimics based upon the structure of Y27632. Sixty compounds were synthesised using amide coupling chemistry and their biological activity tested using various techniques: their ability to restore cell-cell contact growth inhibition in a RhoA-activated cell line; the general cytotoxicity was measured by their ability to inhibit the growth of K562 and A2780 cells; and the effect on the cell cycle analysed using flow cytometry. Three compounds were identified which restored contact inhibition in the RhoA-activated cells while also displaying a low cytotoxicity. These compounds were shown to poorly inhibit ROCK using an ELISA based assay but upon further investigation, they were found to be strongly inhibiting other kinases, namely aurora A (AURKA), p38 (MAPK14) and Hgk (MAP4K4). These compounds represent exciting potential new anti-cancer compounds due to the fact that they inhibit cancer-associated kinases whilst displaying low cytotoxicity.

Item Type:	Thesis (PhD)
Contributors:	Hadfield, JA (Supervisor), Butler, J (Supervisor) and McGown, A (Supervisor)
Schools:	Schools > School of Environment and Life Sciences
Depositing User:	Institutional Repository
Date Deposited:	13 Aug 2021 08:53
Last Modified:	04 Aug 2022 11:22
URI:	https://usir.salford.ac.uk/id/eprint/61514

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