Design of New Potent and Selective Thiophene-Based K V 1.3 Inhibitors and Their Potential for Anticancer Activity.
Simple Summary: In this article, we describe the discovery of a new class of potent and selective thiophene-based inhibitors of the voltage-gated potassium channel KV1.3 and their potential to induce apoptosis and inhibit proliferation. The KV1.3 channel has only recently emerged as a molecular targ...
| Publicado en: | Cancers Vol. 14; no. 11; pp. 2595 - 2615 |
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| Autores principales: | , , , , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
MDPI
Jun2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=157372275&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 157372275 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 20726694 B74B jtl: Cancers issn: 20726694 maglogo: N pubinfo: dt: Jun2022 vid: 14 iid: 11 pid: 97109 pub: MDPI artinfo: ui: 157372275 157372275 157372275 10.3390/cancers14112595 157372275 ppf: 2595 ppct: 20 formats: tig: atl: Design of New Potent and Selective Thiophene-Based K V 1.3 Inhibitors and Their Potential for Anticancer Activity. aug: au: Gubič, Špela Hendrickx, Louise Antonia Shi, Xiaoyi Toplak, Žan Možina, Štefan Theemsche, Kenny M. Van Pinheiro-Junior, Ernesto Lopes Peigneur, Steve Labro, Alain J. Pardo, Luis A. Tytgat, Jan Tomašič, Tihomir Mašič, Lucija Peterlin affil: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia sug: subj: Neoplasms Drug Therapy Sulfur Compounds Therapeutic Use Potassium Channel Blockers Pharmacodynamics Antineoplastic Agents Pharmacodynamics Drug Design Animal Studies Molecular Structure Cell Proliferation Apoptosis ab: Simple Summary: In this article, we describe the discovery of a new class of potent and selective thiophene-based inhibitors of the voltage-gated potassium channel KV1.3 and their potential to induce apoptosis and inhibit proliferation. The KV1.3 channel has only recently emerged as a molecular target in cancer therapy. The most potent KV1.3 inhibitor 44 had an IC50 KV1.3 value of 470 nM (oocytes) and 950 nM (Ltk− cells) and appropriate selectivity for other KV channels. New KV1.3 inhibitors significantly inhibited proliferation of Panc-1 cells and KV1.3 inhibitor 4 induced significant apoptosis in tumor spheroids of Colo-357 cells. The voltage-gated potassium channel KV1.3 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 KV1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency and selectivity of the new KV1.3 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 KV1.3 inhibitor 44 in the series with an IC50 value of 470 nM in oocytes and 950 nM in Ltk− cells. KV1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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