New Diarylamine K10.1 Inhibitors and Their Anticancer Potential.

Expression of the voltage-gated potassium channel K10.1 (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 K10.1 inhibitors was prepared by structural optimisation and exploration of the structure-activity relationship of the previously published hit compound ZVS-08 () and its optimised analogue . The potency and selectivity of the new inhibitors between K10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K10.1 inhibitors, and , with improved nanomolar IC values of 568 nM and 214 nM, respectively. Compound exhibited better ratio between IC values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds and moderately inhibited the growth of the K10.1-expressing cell line MCF-7 in two independent assays. In addition, and 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 K10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future.