Design of New Potent and Selective Thiophene-Based K1.3 Inhibitors and Their Potential for Anticancer Activity.

The voltage-gated potassium channel K1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of K1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency and selectivity of the new K1.3 inhibitors were investigated using whole-cell patch- and voltage-clamp experiments. 2D and 3D cell models were used to determine antiproliferative activity. Structural optimization resulted in the most potent and selective K1.3 inhibitor in the series with an IC value of 470 nM in oocytes and 950 nM in Ltk cells. K1.3 inhibitor induced significant apoptosis in Colo-357 spheroids, while , , , and significantly inhibited Panc-1 proliferation.