Žan Toplak (Avtor), Louise Antonia Hendrickx (Avtor), Špela Gubič (Avtor), Štefan Možina (Avtor), Bojana Žegura (Avtor), Alja Štraser (Avtor), Matjaž Novak (Avtor), Xiaoyi Shi (Avtor), Tihomir Tomašić (Avtor), Lucija Peterlin-Mašič (Avtor)

Povzetek

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 [micro]M 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.

Ključne besede

KV10.1;ion channels;hERG;pharmacophore modelling;virtual screening;antiproliferative activity;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.4:54:616-006
COBISS: 55144451 Povezava se bo odprla v novem oknu
ISSN: 2072-6694
Št. ogledov: 182
Št. prenosov: 53
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: ionski kanal;virtualno rešetanje;tumorski markerji;farmakoforno modeliranje;Kv10.1;antiproliferativno delovanje;Farmacevtska kemija;Tumorski označevalci;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-24
Letnik: ǂVol. ǂ13
Zvezek: ǂiss. ǂ6
Čas izdaje: 2021
DOI: 10.3390/cancers13061244
ID: 14545342