title: The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. suzanne.wardell@duke.edu
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077267:Fulvestrant; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D007976:Leupeptins; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde