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 ESR1 Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
Since the PBPK model can capture the diverse temporal profiles of non-targeted nanoparticles, we propose that when specific binding ligands are lacking, size and charge of nanodevices govern most of their in vivo interactions.
Estrogen
receptor alpha (ERα) is a well-validated drug target
for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to
treat ER+ breast cancer and works through two mechanismsas
a full antagonist and selective estrogen receptor degrader (SERD)but
lacks oral bioavailability. Thus, we envisioned a “best-in-class”
molecule with the same dual mechanisms as fulvestrant, but with significant
oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative
activity in both MCF7 and T47D cells. To illustrate the binding mode
and key interactions of this scaffold with ERα, we obtained
a cocrystal structure of 6 that showed ionic interaction
of azetidine with Asp351 residue. Importantly, 12 showed
favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust
dose-dependent efficacy in xenograft models.
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