Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity
| Autor: | Leslie Hodges-Gallagher, David C. Myles, C.E. Fowler, Geoffrey L. Greene, R. Sun, Isaac N. Plant, Bradley Green, Cyrus L. Harmon, Sean W. Fanning, Peter J. Kushner |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist Protein Conformation alpha-Helical Selective Estrogen Receptor Modulators Pyrrolidines medicine.drug_class Science General Physics and Astronomy Estrogen receptor Mice Nude Antineoplastic Agents General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Protein structure medicine Structure–activity relationship Animals Humans Benzopyrans lcsh:Science skin and connective tissue diseases Cell Proliferation Mice Inbred BALB C Multidisciplinary Cell growth Chemistry Uterus Estrogen Antagonists Estrogen Receptor alpha Mammary Neoplasms Experimental Stereoisomerism General Chemistry Antiestrogen Alkaline Phosphatase Xenograft Model Antitumor Assays 030104 developmental biology Selective estrogen receptor modulator 030220 oncology & carcinogenesis Cancer research MCF-7 Cells lcsh:Q Female Estrogen receptor alpha hormones hormone substitutes and hormone antagonists |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-12 (2018) |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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