Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer

• Published in: Journal of medicinal chemistry 2018-09, Vol.61 (17), p.7917-7928
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00921

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.