Store-operated channels (SOC) are necessary for the function of immune cells, and mutations in such channels are linked to severe immunodeficiency. In immune cells, calcium flux is regulated by SOC Orai1, which is activated by the binding of STIM1. The small molecule AnCoA4 binds the C-terminus of Orai1 directly (SMM, SPR, fluorescence aggregation assay), and exhibits an IC50 of 0.88µM in an NFAT reporter assay. AnCoA4 disrupts the binding of STIM1 to Orai1 leading to decreased SOC channel activation, and prevents calcium influx through the channel thereby inhibiting T cell activation both in vitro and in vivo. Sadaghiani et al., Chem. Biol. 10, 1278-1292, 2014.