Allosteric Induction of Estrogen Receptor Ligand Binding Domain Tetramerization by a Distinct Complete Estrogen Receptor Antagonist

ACS Medicinal Chemistry Letters 2026 Open access

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Authors: Emma C. Fink, Reena Chawla, Govinda R Hancock, Kylie S. Wells, Susanna A. Barratt, David C. Myles, Guadalupe Peña, Brandon Robello, Brian R. Hearn, Sean William Fanning
DOI: 10.1021/acsmedchemlett.5c00667
Cited by: 1
References: 41

Abstract

High Resolution Image Download MS PowerPoint Slide Complete estrogen receptor antagonists (CERANs) are effective against advanced estrogen receptor-positive (ER+) breast cancers, but current chemical scaffolds limit our ability to explore the full range of ER pharmacology. We report the synthesis of OP-1690 ( 2 ), a CERAN featuring a distinct unconstrained core. Structural and biophysical studies reveal that 2 uniquely promotes estrogen receptor alpha (ERα) ligand binding domain (LBD) tetramer formation, which goes beyond the conventional homodimer. This study shows how new CERAN scaffolds can reveal unrecognized mechanisms of action.

Fields of Study & Subjects

Estrogen and related hormone effects Ferrocene Chemistry and Applications Prostate Cancer Treatment and Research

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Volume
17
Issue
2
Pages
441–449
Publication date
16 January 2026
Language
EN