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

Kemp, TP

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.

Citation

Kemp, T. Synthesis and evaluation of novel kinase inhibitors as anti-cancer agents. (Thesis). University of Salford

• Thesis Type: Thesis
• Deposit Date: Aug 13, 2021
• Award Date: Jan 1, 2012