Abstract:
Checkpoint kinase 1 (Chk1, CHEK1) is a Ser/Thr protein kinase that plays a key role in mediating the cellular response to DNA-damage. Currently, there is no drug on the market for Chk1. Therefore, a virtual high throughput screen was conducted to find suitable lead compounds. Eighteen compounds were selected as potential candidates and sent for cancer cell line screening at the US National Cancer Institute. Compound 7903694 returned the greatest activity with a LC50 of 9.35μM for the COLO 205 cell line of the colon cancer panel. Further testing on compound 5473878 is still underway. Phospholipase C - γ (PLC-γ) has been identified as a potential target for anticancer therapy. There are two isoforms of this protein, both lacking in suitable inhibitors. In order to identify a lead compound a structure activity relationship (SAR) for the quinoline-2-carboxamide family was performed along with a virtual high throughput screen. Compound L224982 disproved the current SAR by showing a promising mean growth inhibition of 69.7% at 10μM without the lysine 438 hydrogen bond interaction thought to be critical. Results for compound 2S-85505 displayed with a mean growth inhibition of 83.6% at 10μM suggesting that the positions of X2 and X3 on the phenyl ring show the greatest activity. Further cancer cell experimentation is underway for six of this class of compounds. Six compounds developed by the virtual high throughput screen showed selective inhibition specifically for the leukaemia panel. This is believed to be an indication of binding selectively to the PLC-γ2 isoform expressed only in haematopoietic cells.