Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927
Year: 2018
Type: article
Abstract: The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha . In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.
Source: ACS Medicinal Chemistry Letters
Authors: Mehmet Kahraman, Steven P. Govek, Johnny Y. Nagasawa, Andiliy Lai, Celine Bonnefous, Karensa Douglas, John Sensintaffar, Nhin Liu, KyoungJin Lee, Anna Aparicio, Josh Kaufman, Jing Qian, Gang Shao, Rene Prudente, James D. Joseph, Beatrice Darimont, Daniel Brigham, Richard Heyman, Peter J. Rix, Jeffrey H. Hager, Nicholas D. Smith
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2904445846