Estrogen receptor covalent antagonists: the best is yet to come

Abstract

The development of tamoxifen and subsequent estrogen receptor alpha (ERa) antagonists represents a tremendous therapeutic breakthrough in the treatment of breast cancer. Despite the ability of ERa 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 ERa, remain dependent on ERa 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 ERa 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.