3D Pharmacophore-Based Discovery of Novel K V 10.1 Inhibitors with Antiproliferative Activity.
Simple Summary: A novel structural class of inhibitors of the voltage-gated potassium channel KV10.1 was discovered by a ligand-based drug design method using a 3D pharmacophore model. The virtual screening hit compound ZVS-08 inhibited the channel in a voltage-dependent manner consistent with the a...
| Publicado en: | Cancers Vol. 13; no. 6; pp. 1244 - 1245 |
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| Autores principales: | , , , , , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
MDPI
Mar2021
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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=149619179&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 149619179 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 20726694 B74B jtl: Cancers issn: 20726694 maglogo: N pubinfo: dt: Mar2021 vid: 13 iid: 6 pid: 97109 pub: MDPI artinfo: ui: 149619179 149619179 149619179 10.3390/cancers13061244 149619179 ppf: 1244 ppct: 1 formats: tig: atl: 3D Pharmacophore-Based Discovery of Novel K V 10.1 Inhibitors with Antiproliferative Activity. aug: au: Toplak, Žan Hendrickx, Louise Antonia Gubič, Špela Možina, Štefan Žegura, Bojana Štern, Alja Novak, Matjaž Shi, Xiaoyi Peigneur, Steve Tytgat, Jan Tomašič, Tihomir Pardo, Luis A. Mašič, Lucija Peterlin Roszik, Jason affil: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia sug: subj: Drug Discovery Membrane Transport Proteins Antagonists and Inhibitors Membrane Glycoproteins Antagonists and Inhibitors Antineoplastic Agents Pharmacokinetics Cell Proliferation Drug Effects Pharmacophore Human Molecular Structure Ligands Chemistry, Pharmaceutical Models, Structural Health Screening Cell Line, Tumor Gene Expression Apoptosis ab: Simple Summary: A novel structural class of inhibitors of the voltage-gated potassium channel KV10.1 was discovered by a ligand-based drug design method using a 3D pharmacophore model. The virtual screening hit compound ZVS-08 inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structure–activity relationship studies revealed a nanomolar KV10.1 inhibitor that is selective for some KV and NaV channels but exhibits significant inhibition of the hERG channel. KV10.1 inhibitor 1 inhibited the growth of the MCF-7 cell line expressing high levels of KV10.1 and low levels of hERG more potently than the Panc1 cell line (no KV10.1 and high hERG expression). Moreover, the KV10.1 inhibitor 1 induced significant apoptosis in tumour spheroids of Colo-357 cells. This study may provide a basis for the use of computational drug design methods for the discovery of novel KV10.1 inhibitors as new promising anticancer drugs. (1) Background: The voltage-gated potassium channel KV10.1 (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 KV10.1 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 IC50 value of 3.70 µM against KV10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent KV10.1 inhibitor of the series with an IC50 value of 740 nM, which was potent on the MCF-7 cell line expressing high KV10.1 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 KV10.1 inhibitors. The main problem in the field of KV10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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