- Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer
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About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.
- Nagasawa, Johnny,Govek, Steven,Kahraman, Mehmet,Lai, Andiliy,Bonnefous, Celine,Douglas, Karensa,Sensintaffar, John,Lu, Nhin,Lee, Kyoungjin,Aparicio, Anna,Kaufman, Josh,Qian, Jing,Shao, Gang,Prudente, Rene,Joseph, James D.,Darimont, Beatrice,Brigham, Daniel,Maheu, Kate,Heyman, Richard,Rix, Peter J.,Hager, Jeffrey H.,Smith, Nicholas D.
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supporting information
p. 7917 - 7928
(2018/09/06)
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- ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
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Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
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Page/Page column 105
(2012/01/05)
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- Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers
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A series of benzoxathiin SERAMs was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue. A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
- Blizzard, Timothy A.,Dininno, Frank,Morgan II, Jerry D.,Chen, Helen Y.,Wu, Jane Y.,Kim, Seongkon,Chan, Wanda,Birzin, Elizabeth T.,Yang, Yi Tien,Pai, Lee-Yuh,Fitzgerald, Paula M.D.,Sharma, Nandini,Li, Ying,Zhang, Zhoupeng,Hayes, Edward C.,Dasilva, Carolyn A.,Tang, Wei,Rohrer, Susan P.,Schaeffer, James M.,Hammond, Milton L.
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p. 107 - 113
(2007/10/03)
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- Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 3. Enhancing activity by imposing conformational restriction in the C-4'' side chain
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The preparation and biological evaluation of a series of benzo[b]thiophene diamine thrombin inhibitors possessing conformationally restricted C-4'' linkers are reported. Compared to the parent compounds 1a/b, the unsaturated derivatives 3a/b exhibited a m
- Bastian, Jolie A.,Chirgadze, Nickolay,Denney, Michael L.,Gifford-Moore, Donetta S.,Sall, Daniel J.,Smith, Gerald F.,Wikel, James H.
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p. 363 - 368
(2007/10/03)
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