Design of New Potent and Selective Thiophene-Based K_V1.3 Inhibitors and Their Potential for Anticancer Activity

The voltage-gated potassium channel K_V1.3 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 K_V1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency and selectivity of the new K_V1.3 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 K_V1.3 inhibitor 44 in the series with an IC₅₀ value of 470 nM in oocytes and 950 nM in Ltk^- cells. K_V1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation.