Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927
| Autor: | Celine Bonnefous, Steven P. Govek, James Joseph, Nicholas D. Smith, Kyoung-Jin Lee, John Sensintaffar, Jeffrey H. Hager, Karensa L. Douglas, Andiliy G. Lai, Daniel Brigham, Richard A. Heyman, Johnny Y. Nagasawa, Mehmet Kahraman, Nhin Liu, Jing Qian, Anna Aparicio, Josh Kaufman, Gang Shao, Rene Prudente, Peter J. Rix, Beatrice Darimont |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.drug_class business.industry Organic Chemistry Antagonist Estrogen receptor Breast Cancer Model medicine.disease 01 natural sciences Biochemistry Tamoxifen resistant 0104 chemical sciences Clinical trial 010404 medicinal & biomolecular chemistry 03 medical and health sciences 030104 developmental biology Breast cancer Estrogen Drug Discovery Cancer research medicine Degradation (geology) business |
| Zdroj: | ACS Medicinal Chemistry Letters. 10:50-55 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.8b00414 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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