It has become apparent of late that even in tamoxifen and/or aromatase resistant 
breast cancers, ERα remains a bona fide therapeutic target. Not surprisingly, 
therefore, there has been considerable interest in developing Selective ER 
Degraders (SERDs), compounds that target the receptor for degradation. 
Currently, ICI 182,780 (ICI, fulvestrant) is the only SERD approved for the 
treatment of breast cancer. However, the poor pharmaceutical properties of this 
injectable drug and its lack of superiority over second line aromatase 
inhibitors in late stage breast cancer have negatively impacted its clinical 
use. These findings have provided the impetus to develop second generation, 
orally bioavailable SERDs with which quantitative turnover of ERα in tumors can 
be achieved. Interestingly however, the contribution of SERD activity to 
fulvestrant efficacy is unclear, making it difficult to define the 
characteristics desired of the next generation of ER antagonists. It is of 
significance therefore, that we have determined that the antagonist activity of 
ICI and its ability to induce ERα degradation are not coupled processes. 
Specifically, our results indicate that it is the ability of ICI to interact 
with ERα and to (a) competitively displace estradiol and (b) induce a 
conformational change in ER incompatible with transcriptional activation that 
are likely to be the most important pharmacological characteristics of this 
drug. Collectively, these data argue for a renewed emphasis on the development 
of high affinity, orally bioavailable pure antagonists and suggest that SERD 
activity though proven effective may not be required for ERα antagonism in 
breast cancer.