GDC-9545 (Giredestrant):
A Potent and Orally Bioavailable
Selective Estrogen Receptor Antagonist and Degrader with an Exceptional
Preclinical Profile for ER+ Breast Cancer
posted on 2021-07-12, 16:08authored byJun Liang, Jason R. Zbieg, Robert A. Blake, Jae H. Chang, Stephen Daly, Antonio G. DiPasquale, Lori S. Friedman, Thomas Gelzleichter, Matthew Gill, Jennifer M. Giltnane, Simon Goodacre, Jane Guan, Steven J. Hartman, Ellen Rei Ingalla, Lorn Kategaya, James R. Kiefer, Tracy Kleinheinz, Sharada S. Labadie, Tommy Lai, Jun Li, Jiangpeng Liao, Zhiguo Liu, Vidhi Mody, Neville McLean, Ciara Metcalfe, Michelle A. Nannini, Jason Oeh, Martin G. O’Rourke, Daniel F. Ortwine, Yingqing Ran, Nicholas C. Ray, Fabien Roussel, Amy Sambrone, Deepak Sampath, Leah K. Schutt, Maia Vinogradova, John Wai, Tao Wang, Ingrid E. Wertz, Jonathan R. White, Siew Kuen Yeap, Amy Young, Birong Zhang, Xiaoping Zheng, Wei Zhou, Yu Zhong, Xiaojing Wang
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.