Agents that inhibit estrogen production, such as aromatase inhibitors or those 
that directly block estrogen receptor (ER) activity, such as selective estrogen 
receptor modulators and selective estrogen receptor degraders, are routinely 
used in the treatment of ER-positive breast cancers. However, although initial 
treatment with these agents is often successful, many women eventually relapse 
with drug-resistant breast cancers. To overcome some of the challenges 
associated with current endocrine therapies and to combat the development of 
resistance, there is a need for more durable and more effective ER-targeted 
therapies. Here we describe and characterize a novel, orally bioavailable 
small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its 
therapeutic potential for the treatment of breast cancer. RAD1901 selectively 
binds to and degrades the ER and is a potent antagonist of ER-positive breast 
cancer cell proliferation. Importantly, RAD1901 produced a robust and profound 
inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 
model, RAD1901-treated animals survived longer than those treated with either 
control or fulvestrant, suggesting the potential benefit of RAD1901 in the 
treatment of ER-positive breast cancer that has metastasized to the brain. 
Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the 
uterotropic effects of E2, suggesting that it may act selectively as an agonist 
in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently 
under clinical study in postmenopausal women with ER-positive advanced breast 
cancer.