Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 16, Pages 11841-11856Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00847
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Funding
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P30GM133894]
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The discovery of clinical candidate 35 (GDC-9545 or giredestrant) as an efficient and potent selective estrogen receptor degrader (SERD) and full antagonist has shown promising results in preclinical studies, demonstrating low drug-drug interaction liability and excellent safety profiles. This compound is currently undergoing Phase III clinical trials for the treatment of breast cancer.
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 ER alpha tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
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