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.

Dynamics Insights Into the Gain of Flexibility by Helix-12 in ESR1 as a Mechanism of Resistance to Drugs in Breast Cancer Cell Lines

“…Furthermore, other hydrophobic and electrostatic interactions are also formed and lost. It is also important that targeting Cys530 residue could help in resolving the resistance posed by these mutations (Furman et al, 2019). The number of hydrogen bonds before and after the MD simulation and their lengths are given in Table S2.…”

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

“…However, H3B-5942 could result in Cys530 mutation resulting in decreased efficacy of the drug [281]. The effects of this compound on all known forms of ERα mutants are not yet known and may result in resistance via non-genomic signaling as seen in the case of tamoxifen resistance [282].…”

Invited Review: The role and contribution of transcriptional enhancers in brain cancer

“…In the cases when this is possible, ‘drugging’ specific TFs can have profound effects on tumour growth. Key examples are seen in hormone‐driven breast and prostate cancers where oestrogen and androgen receptor proteins, which serve as TFs, can be inhibited effectively by small molecules [57]. Another instance is arsenic trioxide mediated degradation of PML protein in PML‐RARA fused leukaemia [58].…”