학술논문
GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer
Document Type
Article
Author
Liang, Jun; Zbieg, Jason R.; Blake, Robert A.; Chang, Jae H.; Daly, Stephen; DiPasquale, Antonio G.; Friedman, Lori S.; Gelzleichter, Thomas; Gill, Matthew; Giltnane, Jennifer M.; Goodacre, Simon; Guan, Jane; Hartman, Steven J.; Ingalla, Ellen Rei; Kategaya, Lorn; Kiefer, James R.; Kleinheinz, Tracy; Labadie, Sharada S.; Lai, Tommy; Li, Jun; Liao, Jiangpeng; Liu, Zhiguo; Mody, Vidhi; McLean, Neville; Metcalfe, Ciara; Nannini, Michelle A.; Oeh, Jason; O’Rourke, Martin G.; Ortwine, Daniel F.; Ran, Yingqing; Ray, Nicholas C.; Roussel, Fabien; Sambrone, Amy; Sampath, Deepak; Schutt, Leah K.; Vinogradova, Maia; Wai, John; Wang, Tao; Wertz, Ingrid E.; White, Jonathan R.; Yeap, Siew Kuen; Young, Amy; Zhang, Birong; Zheng, Xiaoping; Zhou, Wei; Zhong, Yu; Wang, Xiaojing
Source
Journal of Medicinal Chemistry; 20210101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
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). 35is 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 35in preclinical species and humans. 35exhibits low drug–drug interaction liability and demonstrates excellent in vitroand in vivosafety profiles. At low doses, 35induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537Smutant PDX or a wild-type ERα tumor model. Currently, 35is being evaluated in Phase III clinical trials.