Martina Piga (Avtor), Zoltán Varga (Avtor), Ádám Fehér (Avtor), Ferenc Papp (Avtor), Eva Korpos Pintye-Gyuri (Avtor), Kavya C. Bangera (Avtor), Rok Frlan (Avtor), Janez Ilaš (Avtor), Jaka Dernovšek (Avtor), Tihomir Tomašić (Avtor), Nace Zidar (Avtor)

Povzetek

The human voltage-gated proton channel, hHv1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of Hv1 has been shown to promote tumor formation by highly metastatic cancer cells, and has been associated with neuroinflammatory diseases, immune response disorders and infertility, suggesting a potential use of hHv1 inhibitors in numerous therapeutic areas. To identify compounds targeting this channel, we performed a structure-based virtual screening on an open structure of the human Hv1 channel. Twenty selected virtual screening hits were tested on Chinese hamster ovary (CHO) cells transiently expressing hHv1, with compound 13 showing strong block of the proton current with an IC50 value of 8.5 μM. Biological evaluation of twenty-three additional analogs of 13 led to the discovery of six other compounds that blocked the proton current by more than 50% at 50 μM concentration. This allowed for an investigation of structure–activity relationships. The antiproliferative activity of the selected promising hHv1 inhibitors was investigated in the cell lines MDA-MB-231 and THP-1, where compound 13 inhibited growth with an IC50 value of 9.0 and 8.1 μM, respectively. The identification of a new structural class of Hv1 inhibitors contributes to our understanding of the structural requirements for inhibition of this ion channel and opens up the possibility of investigating the role of Hv1 inhibitors in various pathological conditions and in cancer therapy.

Ključne besede

cancer;cells;inhibition;inhibitors;screening assays;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 616-07:616-006
COBISS: 199158019 Povezava se bo odprla v novem oknu
ISSN: 1549-960X
Št. ogledov: 85
Št. prenosov: 15
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: celice;inhibicija;inhibitorji;presejalni testi;Rak (medicina);
Vrsta dela (COBISS): Članek v reviji
Strani: <v tisku>
Letnik: ǂVol. ǂ
Zvezek: ǂiss. ǂ
Čas izdaje: 2024
DOI: 10.1021/acs.jcim.4c00240
ID: 24473674