20.500.12556/RUL-134993 3D pharmacophore-based discovery of novel Kv10.1 inhibitors with antiproliferative activity (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$10.1 and inhibited the channel in a voltagedependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent K$_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$10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods. K$_V$10.1 ion channels hERG pharmacophore modelling virtual screening antiproliferative activity K$_V$10.1 ionski kanal tumorski markerji farmakoforno modeliranje virtualno rešetanje antiproliferativno delovanje farmacevtska kemija tumorski označevalci true false true Angleški jezik Slovenski jezik Članek v reviji 2022-02-16 14:03:00 2022-02-16 14:03:05 2022-09-14 04:11:04 0000-00-00 00:00:00 2021 0 0 24 str. iss. 6, art. 1244 Vol. 13 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616-006 2072-6694 10.3390/cancers13061244 55144451 RAZ_Toplak_Zan_2021.pdf RAZ_Toplak_Zan_2021.pdf 1 D9BDDEEF154742BC3D98610B72F86623 91c46161080730747b9982f51c197c9e97bc96a678644c8b74d52c4ae09684b6 e9d7a1ed-8f28-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=153796 https://www.mdpi.com/2072-6694/13/6/1244 1 8b00f24e-8f28-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=153795 Fakulteta za farmacijo 0 0 0