New diarylamine KV10.1 inhibitors and their anticancer potential

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

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.

• Language: English
• Keywords: KV10.1, ion channels, hERG, SAR, 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: 2022
• Number of pages: 27 str.
• Numbering: Vol. 14, iss. 8, art. 1963
• PID: 20.500.12556/RUL-140829
• UDC: 577.352
• ISSN on article: 1999-4923
• DOI: 10.3390/pharmaceutics14091963
• COBISS.SI-ID: 121841667
• Publication date in RUL: 19.09.2022

Record is a part of a journal

• Title: Pharmaceutics
• Shortened title: Pharmaceutics
• Publisher: MDPI
• ISSN: 1999-4923
• COBISS.SI-ID: 517949977

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: 19.09.2022

Secondary language

• Language: Slovenian
• Keywords: KV10.1, ionski kanali, hERG, SAR, antiproliferativno delovanje

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: N1-0098-2019
• Name: Odkrivanje in mehanizem delovanja novih spojin vodnic hEag1 kalijevih kanalov s protirakavim delovanjem

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208-2022
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin