Design of new potent and selective thiophene-based K$_V$1.3 inhibitors and their potential for anticancer activity

Gubič, Špela (author), Toplak, Žan (author), Možina, Štefan (author), Tomašič, Tihomir (author), Peterlin-Mašič, Lucija (author)

The voltage-gated potassium channel K$_V$1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of K$_V$1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency and selectivity of the new K$_V$1.3 inhibitors were investigated using whole-cell patch- and voltage-clamp experiments. 2D and 3D cell models were used to determine antiproliferative activity. Structural optimization resulted in the most potent and selective K$_V$1.3 inhibitor 44 in the series with an IC$_{50}$ value of 470 nM in oocytes and 950 nM in Ltk$^−$ cells. K$_V$1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation.

• Language: English
• Keywords: K$_V$1.3, potassium ion channels, antiproliferative activity, apoptosis, anticancer drugs
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 20 str.
• Numbering: Vol. 14, iss. 11, art. 2595
• PID: 20.500.12556/RUL-145179
• UDC: 615.277.3:576.36
• ISSN on article: 2072-6694
• DOI: 10.3390/cancers14112595
• COBISS.SI-ID: 109409795
• Publication date in RUL: 12.04.2023

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.

Secondary language

• Language: Slovenian
• Keywords: K$_V$1.3, kalijevi ionski kanali, antiproliferativno delovanje, zdravila proti raku, rak, apoptoza, farmacevtska kemija