Dual-Mechanism Estrogen Receptor Inhibitors Reveal an Ensemble of Binding Modes for Robust Breast Cancer Antagonism

Current antiestrogen therapies for estrogen receptor alpha (ERa)-positive breast cancers work only by direct antagonism, using a single side chain that extends outward from the ligand core to disrupt the transcriptional coactivator-binding site via a direct steric interaction that requires precise chemical targeting. Here, we present a new class of antiestrogens with a 7-oxa-bicyclo[2.2.1]heptene sulfonamide core that combines direct antagonism with indirect antagonism, to also modulate the coactivator-binding site indirectly. These dual-mechanism ER inhibitors (DMERIs) fully antagonized the proliferation of breast cancer cells, including tamoxifen-resistant models, irrespective of their side chain structure and substitution site. These inhibitors displayed an ensemble of binding modes and associated receptor conformational sub-states that drive their unique properties, verified with solution structural probes. Dualmechanism inhibitors of ERα thus represent an approach to therapeutic targeting with robust efficacy, novel binding modes and associated structural perturbations, and greater tolerance for chemical variety in ligand design.Competing Interest StatementJAK is a founder and stockholder of Radius Health Inc. and a consultant of Celcuity Inc. BSK is a consultant of Celcuity Inc.View Full Text