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

Disruption of protein kinase signalling pathways is often associated with cancer. TheRhoA/ROCK kinase pathway has been shown to be constitutively expressed in many cancersand has also been shown to be involved in metastasis and apoptosis. ROCK is inhibited bythe ATP mimic Y27632, which competitively binds the ATP binding site. All protein kinasespossess an ATP binding pocket and subtle differences in these pockets can allow thedevelopment of highly selective ATP mimicking inhibitors.The major part of my research was to identify novel kinase inhibitor anti-cancer agents bysynthesising ATP mimics based upon the structure of Y27632. Sixty compounds weresynthesised using amide coupling chemistry and their biological activity tested using varioustechniques: their ability to restore cell-cell contact growth inhibition in a RhoA-activated cellline; the general cytotoxicity was measured by their ability to inhibit the growth of K562 andA2780 cells; and the effect on the cell cycle analysed using flow cytometry.Three compounds were identified which restored contact inhibition in the RhoA-activatedcells while also displaying a low cytotoxicity. These compounds were shown to poorlyinhibit ROCK using an ELISA based assay but upon further investigation, they were found tobe strongly inhibiting other kinases, namely aurora A (AURKA), p38 (MAPK14) and Hgk(MAP4K4). These compounds represent exciting potential new anti-cancer compounds dueto the fact that they inhibit cancer-associated kinases whilst displaying low cytotoxicity.

Level dc:type.qualificationlevel

Doctoral (Level 8)

Year dc:date.issued

2012

Author dc:creator

• Kemp, TP

Language dc:language

en

Identifier

oai:salford-repository.worktribe.com:1337512

OAI identifier oai:identifier

oai:salford-repository.worktribe.com:1337512