Špela Gubič (Author), Žan Toplak (Author), Xiaoyi Shi (Author), Jaka Dernovšek (Author), Louise Antonia Hendrickx (Author), Ernesto Lopes Pinheiro-Junior (Author), Steve Peigneur (Author), Jan Tytgat (Author), Luis A. Pardo (Author), Lucija Peterlin-Mašič (Author), Tihomir Tomašić (Author)

Abstract

Expression of the voltage-gated potassium channel KV10.1 (Eag1) has been detected in over 70% of human cancers, making the channel a promising new target for new anticancer drug discovery. A new structural class of KV10.1 inhibitors was prepared by structural optimisation and exploration of the structure–activity relationship of the previously published hit compound ZVS-08 (1) and its optimised analogue 2. The potency and selectivity of the new inhibitors between KV10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised KV10.1 inhibitors, 17a and 18b, with improved nanomolar IC50 values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC50 values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the KV10.1-expressing cell line MCF-7 in two independent assays. In addition, 17a and 18b also inhibited the growth of hERG-expressing Panc-1 cells with higher potency compared with MCF-7 cells. The main obstacle for newly developed diarylamine KV10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future.

Keywords

KV10.1;ionski kanali;hERG;SAR;antiproliferativno delovanje;ion channels;antiproliferative activity;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 577.352
COBISS: 121841667 Link will open in a new window
ISSN: 1999-4923
Views: 6
Downloads: 3
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Other data

Secondary language: Slovenian
Secondary keywords: Ionski kanalčki;
Type (COBISS): Article
Pages: 27 str.
Volume: ǂVol. ǂ14
Issue: ǂiss. ǂ8, art. 1963
Chronology: 2022
DOI: 10.3390/pharmaceutics14091963
ID: 16506308