3D pharmacophore-based discovery of novel Kv10.1 inhibitors with antiproliferative activity

Toplak, Žan (author), Hendrickx, Louise Antonia (author), Gubič, Špela (author), Možina, Štefan (author), Žegura, Bojana (author), Štern, Alja (author), Novak, Matjaž (author), Shi, Xiaoyi (author), Peigneur, Steve (author), Tytgat, Jan (author), Tomašič, Tihomir (author), Pardo, Luis A. (author), Peterlin-Mašič, Lucija (author)

(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.

• Language: English
• Keywords: K$_V$10.1, ion channels, hERG, pharmacophore modelling, virtual screening, antiproliferative activity
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 24 str.
• Numbering: Vol. 13, iss. 6, art. 1244
• PID: 20.500.12556/RUL-134993
• UDC: 615.4:54:616-006
• ISSN on article: 2072-6694
• DOI: 10.3390/cancers13061244
• COBISS.SI-ID: 55144451
• Publication date in RUL: 16.02.2022

Record is a part of a journal

• Title: Cancers
• Shortened title: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• COBISS.SI-ID: 517914137

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 12.03.2021

Secondary language

• Language: Slovenian
• Keywords: K$_V$10.1, ionski kanal, tumorski markerji, farmakoforno modeliranje, virtualno rešetanje, antiproliferativno delovanje, farmacevtska kemija, tumorski označevalci