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

  • ACS Med Chem Lett. 2026 Jan 16;17(2):441-449. doi: 10.1021/acsmedchemlett.5c00667.
Emma C Fink  1 ,  Reena Chawla  2 ,  Govinda R Hancock  1 ,  Kylie S Wells  2 ,  Susanna Barratt  2 ,  David C Myles  2 ,  Guadalupe Peña  2 ,  Brandon W Robello  2 ,  Brian R Hearn  2 ,  Sean W Fanning  1
Affiliations
  • 1. Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60546, United States.
  • 2. Olema Oncology, San Francisco, California 94103, United States.
PMID: 41704390 DOI: 10.1021/acsmedchemlett.5c00667
Abstract

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.

Keywords
CERAN; Nuclear receptor; estrogen receptor; hormone; nonsteroidal; oligomerization.
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