Discovery of a highly potent and orally bioavailable Selective Estrogen Receptor Degrader (SERD) GDC-9545 for ER-positive breast cancer

Breast cancer is the most common cancer and second leading cause of cancer death in women. Approximately 70% of breast cancers are ER-positive (ER+). Standard of care therapies include Selective Estrogen Receptor Modulators (SERMs), such as tamoxifen, and aromatase inhibitors. Despite their initial effectiveness, 20-30% of patients eventually relapse, and become resistant due to ER mutations. Fulvestrant, a full antagonist of ER and later found to be a SERD, was approved to treat advanced and metastatic disease. However, fulvestrant is not orally bioavailable and needs to be injected intramuscularly due to its unique pharmacokinetic and pharmaceutical properties. We were attracted by the dual mechanisms of fulvestrant: a full antagonist and an SERD. Herein we report the discovery of GDC-9545, a highly potent full antagonist and orally bioavailable SERD with improved pharmacokinetic and pharmaceutical properties, guided by structure- and property-based designs. In vitro, GDC-9545 showed excellent antagonist potency and consistent ER degradation across ER+ cell lines. In vivo, GDC-9545 demonstrated dose-dependent efficacy in both ER wild-type and mutant xenograft models, achieving tumor regression at 1/100th dose of GDC-0927. Moreover, GDC-9545 did not exhibit partial agonist effect in the uterus of immature rats, and was well tolerated in pilot tox studies. In humans, GDC-9545 showed excellent PK profiles and is currently in Phase III clinical trials.