| Summary: | Expression of the voltage-gated potassium channel K<sub>V</sub>10.1 (Eag1) has been detected in over 70% of human cancers, making the channel a promising new target for new anticancer drug discovery. A new structural class of K<sub>V</sub>10.1 inhibitors was prepared by structural optimisation and exploration of the structure–activity relationship of the previously published hit compound ZVS-08 (<b>1</b>) and its optimised analogue <b>2</b>. The potency and selectivity of the new inhibitors between K<sub>V</sub>10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K<sub>V</sub>10.1 inhibitors, <b>17a</b> and <b>18b</b>, with improved nanomolar IC<sub>50</sub> values of 568 nM and 214 nM, respectively. Compound <b>17a</b> exhibited better ratio between IC<sub>50</sub> values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds <b>17a</b> and <b>18b</b> moderately inhibited the growth of the K<sub>V</sub>10.1-expressing cell line MCF-7 in two independent assays. In addition, <b>17a</b> and <b>18b</b> also inhibited the growth of hERG-expressing Panc-1 cells with higher potency compared with MCF-7 cells. The main obstacle for newly developed diarylamine K<sub>V</sub>10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future.
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