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

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 (<b>2</b>), a CERAN featuring a distinct unconstrained core. Structural and biophysical studies reveal that <b>2</b> 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.