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Tamoxifen and fulvestrant are currently two major approved estrogen receptor-alpha (ER)-targeted therapies for breast cancer, but resistance to their antagonistic actions often develops. Efforts to improve ER-targeted therapies have relied upon a single mechanism, where ligands with a single side chain on the ligand core that extends outward from the ligand binding pocket to directly displace helix (h)12 in the ER ligand-binding domain (LBD), blocking the LBD interaction with transcriptional coactivators that drive proliferation. Here, we describe ER inhibitors that block estrogen-induced proliferation through two distinct structural mechanisms by combining a side chain for direct antagonism with a bulky chemical group that causes indirect antagonism by distorting structural epitopes inside the ligand binding pocket. These dual-mechanism ER inhibitors (DMERIs) fully antagonize the proliferation of wild type ER-positive breast cancer cells and cells that have become resistant to tamoxifen and fulvestrant through activating ER mutations and de novo mechanisms such as overactive growth factor signaling. Conformational probing studies highlight marked differences that distinguish the dual mechanism inhibitors from current standard of care single-mechanism antiestrogens, and crystallographic analyses reveal that they disrupt the positioning of h11 and h12 in multiple ways. Combining two chemical targeting approaches into a single ligand thus provides a flexible platform for next generation ER-targeted therapies. ### 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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