Estrogen Receptor Covalent Antagonists: The Best Is Yet to Come

Cancer Res. 2019 Apr 15;79(8):1740-1745. doi: 10.1158/0008-5472.CAN-18-3634. Epub 2019 Apr 5.


The development of tamoxifen and subsequent estrogen receptor alpha (ERα) antagonists represents a tremendous therapeutic breakthrough in the treatment of breast cancer. Despite the ability of ERα antagonists to increase survival rates, resistance to these therapies is an all-too-common occurrence. The majority of resistant tumors, including those with hotspot mutations in the ligand-binding domain of ERα, remain dependent on ERα signaling, indicating that either a more potent or novel class of antagonist could have clinical benefit. With this thought in mind, we developed a novel ERα antagonist that exhibits enhanced potency due to its ability to covalently target a unique cysteine in ER. This review describes the design of this antagonist, H3B-5942, and discusses opportunities for future improvements, which could reduce the risk of escape mutations to this therapeutic modality.

Publication types

  • Review

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Drug Resistance, Neoplasm / drug effects*
  • Estrogen Receptor Antagonists / therapeutic use*
  • Female
  • Humans
  • Indazoles / therapeutic use*
  • Receptors, Estrogen / antagonists & inhibitors*


  • Estrogen Receptor Antagonists
  • H3B-5942
  • Indazoles
  • Receptors, Estrogen