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Current antiestrogen therapies for estrogen receptor α-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. Dual-mechanism 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 Statement JAK is a founder and stockholder of Radius Health Inc. and a consultant of Celcuity Inc. BSK is a consultant of Celcuity Inc.

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