2-Methoxyestradiol and its derivatives inhibit store-operated Ca2+ entry in T cells: Identification of a new and potent inhibitor

Adhesion to laminin-1 and collagen IV induces the formation of Ca 2+ microdomains that sensitize mouse T cells for activation

“…ORAI1 is a Ca 2+ channel involved in Ca 2+ microdomains in T cells under such weakly adhesive conditions (13,21), a result we confirmed here using Ca 2+ -free buffer (Fig. 1H), the SOCE inhibitor STX564 (22), and the ORAI inhibitor Synta66 (Fig. 1I).…”

2‐Difluoromethoxy‐Substituted Estratriene Sulfamates: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Steroid Sulfatase Inhibition

“…[27] To date this reaction has only been demonstrated for 2ME2, but it seems likely that this could also apply to compounds of the STX140 class, hence the relevance of this current study. Recently, we demonstrated excellent activities for steroidal sulfamates related to STX140 in an in vitro EAE model of MS. [28] The results seem to imply that 2ME2 and related steroid sulfamates can act by blocking calcium entry to lymphocytes, an essential part of the T cell activation process, and that this might be through blockade of the Orai/STIM calcium entry system. [28] Thus, the intrinsic anti-inflammatory activity of 2ME2 [29,30] and STX140 provides significant potential for the compounds as immunomodulatory agents alone or in immuno-oncology.…”

“…Recently, we demonstrated excellent activities for steroidal sulfamates related to STX140 in an in vitro EAE model of MS [28] . The results seem to imply that 2ME2 and related steroid sulfamates can act by blocking calcium entry to lymphocytes, an essential part of the T cell activation process, and that this might be through blockade of the Orai/STIM calcium entry system [28] . Thus, the intrinsic anti‐inflammatory activity of 2ME2 [29,30] and STX140 provides significant potential for the compounds as immunomodulatory agents alone or in immuno‐oncology.…”

2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca2+ entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis

“…The latter study revealed that 2ME2 inhibits T cell activation by impairing the translocation of the transcription factor ‘nuclear factor of activated T cells’ (NFAT) into the nucleus of T cells. More recently, it was shown that 2ME2 and its analogue 2-ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene (STX564) inhibit SOCE through Orai1 channels ( Löhndorf et al ., 2021 ). Thus, inhibition of Ca 2+ entry is likely to be the mechanism underlying 2ME2-mediated inhibition of NFAT translocation, T cell proliferation and cytokine production, as well as G2/M phase cell cycle arrest ( Duncan et al ., 2012 ; Löhndorf et al ., 2021 ).…”