Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts
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- 作者：Andiliy Lai ; Mehmet Kahraman ; Steven Govek ; Johnny Nagasawa ; Celine Bonnefous ; Jackie Julien ; Karensa Douglas ; John Sensintaffar ; Nhin Lu ; Kyoung-jin Lee ; Anna Aparicio ; Josh Kaufman ; Jing Qian ; Gang Shao ; Rene Prudente ; Michael J. Moon ; James D. Joseph ; Beatrice Darimont ; Daniel Brigham ; Kate Grillot ; Richard Heyman ; Peter J. Rix ; Jeffrey H. Hager ; Nicholas D. Smith
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 25, 2015
- 年：2015
- 卷：58
- 期：12
- 页码：4888-4904
- 全文大小：720K
- ISSN：1520-4804
文摘
Approximately 80% of breast cancers are estrogen receptor alpha (ER-伪) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-伪 and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-伪 and in which the ER-伪 degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.