| Autor: |
Piga M; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia., Varga Z; Faculty of Medicine, University of Debrecen, Egyetem tér 1, Debrecen H-4032, Hungary., Feher A; Faculty of Medicine, University of Debrecen, Egyetem tér 1, Debrecen H-4032, Hungary., Papp F; Faculty of Medicine, University of Debrecen, Egyetem tér 1, Debrecen H-4032, Hungary., Korpos E; Faculty of Medicine, University of Debrecen, Egyetem tér 1, Debrecen H-4032, Hungary.; HUN-REN-UD Cell Biology and Signaling Research Group, Egyetem tér 1, Debrecen H-4032, Hungary., Bangera KC; Faculty of Medicine, University of Debrecen, Egyetem tér 1, Debrecen H-4032, Hungary., Frlan R; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia., Ilaš J; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia., Dernovšek J; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia., Tomašič T; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia., Zidar N; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia. |
| Abstrakt: |
The human voltage-gated proton channel, hH V 1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of H V 1 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 hH V 1 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 H V 1 channel. Twenty selected virtual screening hits were tested on Chinese hamster ovary (CHO) cells transiently expressing hH V 1, with compound 13 showing strong block of the proton current with an IC 50 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 hH V 1 inhibitors was investigated in the cell lines MDA-MB-231 and THP-1, where compound 13 inhibited growth with an IC 50 value of 9.0 and 8.1 μM, respectively. The identification of a new structural class of H V 1 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 H V 1 inhibitors in various pathological conditions and in cancer therapy. |
