Blockage of Store-Operated Ca2+ Influx by Synta66 is Mediated by Direct Inhibition of the Ca2+ Selective Orai1 Pore

0534704 - MBÚ 2021 RIV CH eng J - Journal Article
Waldherr, L. - Tiffner, A. - Mishra, Deepti - Sallinger, M. - Schober, R. - Frischauf, I. - Schmidt, T. - Handl, V. - Sagmeister, P. - Kockinger, M. - Derler, I. - Ucal, M. - Bonhenry, Daniel - Patz, S. - Schindl, R.
Blockage of Store-Operated Ca2+ Influx by Synta66 is Mediated by Direct Inhibition of the Ca2+ Selective Orai1 Pore.
Cancers (Basel). Roč. 12, č. 10 (2020), č. článku 2876. E-ISSN 2072-6694
R&D Projects: GA ČR(CZ) GJ19-20728Y
Institutional support: RVO:61388971
Keywords : stim1 * Orai * Ca2+ * Synta66 * pore
OECD category: Cell biology
Impact factor: 6.639, year: 2020
Method of publishing: Open access
https://www.mdpi.com/2072-6694/12/10/2876

Store-operated calcium channels constituted from the proteins Orai and STIM are important targets for development of new drugs, especially for the treatment of auto-immune diseases. Also, interference with channel function is linked to reduced cancer cell progression, making these channels potential targets for anti-cancer drug development. Therefore, inhibitors need to be evaluated for both their binding selectivity and their potential to interfere with cancer progression. Here, we investigated the inhibitor Synta66 and determined its site of binding via both patch clamp recordings and computational approaches and evaluated its potency as anti-cancer agent in glioblastoma multiforme cells. Our findings show that Synta66 is a highly selective ligand to the Orai1 pore and efficiently blocks store operated calcium entry in glioblastoma cells. Still, in the tested cell lines, Synta66 did not reduce cell viability. We therefore suggest Synta66 as a precise tool to observe interference of store-operated Orai1 channel function in vitro and of resulting downstream effects.
The Ca2+ sensor STIM1 and the Ca2+ channel Orai1 that form the store-operated Ca2+ (SOC) channel complex are key targets for drug development. Selective SOC inhibitors are currently undergoing clinical evaluation for the treatment of auto-immune and inflammatory responses and are also deemed promising anti-neoplastic agents since SOC channels are linked with enhanced cancer cell progression. Here, we describe an investigation of the site of binding of the selective inhibitor Synta66 to the SOC channel Orai1 using docking and molecular dynamics simulations, and live cell recordings. Synta66 binding was localized to the extracellular site close to the transmembrane (TM)1 and TM3 helices and the extracellular loop segments, which, importantly, are adjacent to the Orai1-selectivity filter.
Permanent Link: http://hdl.handle.net/11104/0312885