One subclass of
antiestrogens, the selective
estrogen receptor down-regulators (SERDs), have received considerable attention of late as they competitively inhibit
estrogen binding and induce a rapid,
proteasome-dependent degradation of the receptor. Contained within this class of molecules is the steroidal
antiestrogen ICI182,780 (
faslodex), recently approved for the treatment of metastatic
cancer, and
GW5638/DPC974, a SERD that is currently being evaluated in the clinic. Given that mechanistic differences between different
selective estrogen receptor modulators have been translated into important clinical profiles, it was of interest to determine if the SERD subclass of
ligands were likewise functionally or mechanistically distinguishable. In this study, we show that although the steroidal and nonsteroidal SERDs target
ERalpha for degradation, the underlying mechanism(s) are different. Of note was the identification of a specific
protein-
protein interaction surface presented on
ERalpha in the presence of the ICI182,780-activated receptor which is required for degradation. Interestingly, this surface is also presented on
ERalpha in the presence of RU58,668, a SERD that is chemically distinct from ICI182,780. This surface is not required for GW5638-mediated degradation, and thus, this SERD seems to affect
ERalpha down-regulation by a different mechanism. These data suggest that sequencing of
therapies using drugs of this class is likely to be possible. Finally, because of the unmet need for orally active SERDS that function similarly to ICI182,780, we have used the insights from these mechanistic studies to develop and validate a high-throughput screen for compounds of this class with improved
pharmaceutical properties.