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

Biochim Biophys Acta Mol Cell Res. 2021 May;1868(6):118988. doi: 10.1016/j.bbamcr.2021.118988. Epub 2021 Feb 10.


T cell activation starts with formation of second messengers that release Ca2+ from the endoplasmic reticulum (ER) and thereby activate store-operated Ca2+ entry (SOCE), one of the essential signals for T cell activation. Recently, the steroidal 2-methoxyestradiol was shown to inhibit nuclear translocation of the nuclear factor of activated T cells (NFAT). We therefore investigated 2-methoxyestradiol for inhibition of Ca2+ entry in T cells, screened a library of 2-methoxyestradiol analogues, and characterized the derivative 2-ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene (STX564) as a novel, potent and specific SOCE inhibitor. STX564 inhibits Ca2+ entry via SOCE without affecting other ion channels and pumps involved in Ca2+ signaling in T cells. Downstream effects such as cytokine expression and cell proliferation were also inhibited by both 2-methoxyestradiol and STX564, which has potential as a new chemical biology tool.

Keywords: Ca(2+) signaling; ORAI inhibitor; Store-operated Ca(2+) entry; T cell activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Methoxyestradiol / analogs & derivatives
  • 2-Methoxyestradiol / pharmacology*
  • Animals
  • Calcium / metabolism
  • Calcium Signaling / drug effects*
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Estrenes / chemical synthesis
  • Estrenes / chemistry
  • Estrenes / pharmacology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation / drug effects
  • NFATC Transcription Factors / metabolism*
  • Protein Transport / drug effects
  • Rats
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism


  • Estrenes
  • NFATC Transcription Factors
  • 2-Methoxyestradiol
  • Calcium