Abstract
Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.
Highlights
Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer
Our purpose in designing these analogs was to explore the stereochemical space of the antiestrogen side chain shown to be involved in disrupting the active ligand binding domain (LBD) conformation and occlude coactivator binding by repositioning H1225,26,30
Since the stereospecific 3 R orientation of the methylpyrrolidine was shown to be necessary for conferring both pure antiestrogenicity and SERD activity in this series, we explored the molecular interactions with ligand-bound Estrogen Receptor α LBD (ERα) LBD
Summary
Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Selective estrogen receptor modulators (SERMs), such as tamoxifen, exhibit tissue-specific agonist activity in the bone and uterine endometrium but antagonize ER signaling in the breast This partial agonism is implicated in the switch from tamoxifen-responsive tumors to the development of resistance[4,5,6]. SERMs stimulate the transcription of estrogen responsive genes dependent on AF-1, and phosphorylation of AF-1 by growth factors further enhances agonist activity in a ligand-independent manner[9,10] This crosstalk between ERα and growth factor signaling has been shown to play a role in the development of tamoxifen-resistance[11,12,13]. These studies highlight the important nature of H12 as an essential molecular determinant for antiestrogen action, and a more comprehensive understanding of this interaction will aid in designing the generation of inhibitors capable of treating clinical resistance
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