3D Pharmacophore-Based Discovery of Novel K(V)10.1 Inhibitors with Antiproliferative Activity

SIMPLE SUMMARY: A novel structural class of inhibitors of the voltage-gated potassium channel K(V)10.1 was discovered by a ligand-based drug design method using a 3D pharmacophore model. The virtual screening hit compound ZVS-08 inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structure–activity relationship studies revealed a nanomolar K(V)10.1 inhibitor that is selective for some K(V) and Na(V) channels but exhibits significant inhibition of the hERG channel. K(V)10.1 inhibitor 1 inhibited the growth of the MCF-7 cell line expressing high levels of K(V)10.1 and low levels of hERG more potently than the Panc1 cell line (no K(V)10.1 and high hERG expression). Moreover, the K(V)10.1 inhibitor 1 induced significant apoptosis in tumour spheroids of Colo-357 cells. This study may provide a basis for the use of computational drug design methods for the discovery of novel K(V)10.1 inhibitors as new promising anticancer drugs. ABSTRACT: (1) Background: The voltage-gated potassium channel K(V)10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of K(V)10.1 inhibitors. Whole-cell patch clamp experiments were used to investigate potency, selectivity, kinetics and mode of inhibition. Anticancer activity was determined using 2D and 3D cell-based models. (3) Results: The virtual screening hit compound ZVS-08 discovered by 3D pharmacophore modelling exhibited an IC(50) value of 3.70 µM against K(V)10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent K(V)10.1 inhibitor of the series with an IC(50) value of 740 nM, which was potent on the MCF-7 cell line expressing high K(V)10.1 levels and low hERG levels, induced significant apoptosis in tumour spheroids of Colo-357 cells and was not mutagenic. (4) Conclusions: Computational ligand-based drug design methods can be successful in the discovery of new potent K(V)10.1 inhibitors. The main problem in the field of K(V)10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods.