GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer
| Autor: | Martin O'Rourke, Nicholas Charles Ray, Thomas Gelzleichter, Leah Schutt, Ellen Ingalla, Neville James Mclean, Xiaojing Wang, Stephen Daly, Yingqing Ran, Jiangpeng Liao, Tommy Lai, Yu Zhong, Jun Liang, Sharada Labadie, Lori Friedman, Amy Sambrone, Jun Li, Robert A. Blake, Tao Wang, Liu Zhiguo, Birong Zhang, Steven J. Hartman, Jae H. Chang, Wei Zhou, Jane Guan, Vidhi Mody, Jonathan White, Fabien Roussel, Antonio G. DiPasquale, Jason R. Zbieg, Daniel F. Ortwine, Amy Young, James R. Kiefer, Maia Vinogradova, Simon Charles Goodacre, Deepak Sampath, Tracy Kleinheinz, Xiaoping Zheng, Jennifer M. Giltnane, Lorn Kategaya, Ingrid E. Wertz, Matthew Gill, Ciara Metcalfe, Siew Kuen Yeap, John S. Wai, Jason Oeh, Michelle Nannini |
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| Rok vydání: | 2021 |
| Předmět: |
Phases of clinical research
Estrogen receptor Antineoplastic Agents Breast Neoplasms Mice Structure-Activity Relationship Breast cancer Dogs In vivo Drug Discovery medicine Animals Humans Dosing Molecular Structure Chemistry Antagonist Estrogen Receptor alpha medicine.disease Xenograft Model Antitumor Assays In vitro Rats Macaca fascicularis Cell culture Cancer research MCF-7 Cells Molecular Medicine Female Estrogen Receptor Antagonists Carbolines |
| Zdroj: | Journal of medicinal chemistry. 64(16) |
| ISSN: | 1520-4804 |
| Popis: | Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials. |
| Databáze: | OpenAIRE |
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