1区 · 医学
Article
作者: Shao, Gang ; Maheu, Kate ; Rix, Peter J. ; Joseph, James D. ; Govek, Steven ; Kahraman, Mehmet ; Lee, KyoungJin ; Hager, Jeffrey H. ; Qian, Jing ; Sensintaffar, John ; Kaufman, Josh ; Darimont, Beatrice ; Heyman, Richard ; Prudente, Rene ; Nagasawa, Johnny ; Bonnefous, Celine ; Brigham, Daniel ; Aparicio, Anna ; Douglas, Karensa ; Lai, Andiliy ; Smith, Nicholas D. ; Lu, Nhin
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.