Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, 
and although women typically initially respond well to antihormonal therapies 
such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a 
variety of resistance mechanism may be at play in this state, there is evidence 
that in many cases the ER still plays a central role, including mutations in the 
ER leading to constitutively active receptor. Fulvestrant is a steroid-based, 
selective estrogen receptor degrader (SERD) that both antagonizes and degrades 
ER-α and is active in patients who have progressed on antihormonal agents. 
However, fulvestrant suffers from poor pharmaceutical properties and must be 
administered by intramuscular injections that limit the total amount of drug 
that can be administered and hence lead to the potential for incomplete receptor 
blockade. We describe the identification and characterization of a series of 
small-molecule, orally bioavailable SERDs which are potent antagonists and 
degraders of ER-α and in which the ER-α degrading properties were prospectively 
optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust 
activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, 
and is currently in clinical trials in women with locally advanced or metastatic 
estrogen receptor-positive breast cancer.