GDC-0810

GDC-0810 (ARN-810, Brilanestrant) is a non-steroidal, orally bioavailable selective estrogen receptor degrader (SERD) with IC50 of 0.7 nM (ER-α degradation), binds to ERα and ERβ with with Ki of 3.8 and 3.7 nM, respectively; dually antagonizes and induces proteasome-dependent degradation of ERα, exhibits robust in vitro activity against a variety of human breast cancer cell lines (MCF7 cell IC50=25 nM) ; demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer models.Breast Cancer Phase 1 Discontinued (In Vitro) :Brilanestrant (ARN-810; GDC-0810) is a potent ER-α binder (IC50=6.1 nM), a full transcriptional antagonist with no agonism (3x ERE, IC50=2 nM), and displays good potency and efficacy in ER-α degradation (EC50=0.7 nM) and MCF-7 breast cancer cell viability (IC50=2.5 nM) assays.Brilanestrant (ARN-810; GDC-0810) induces a distinct ERα conformation versus tamoxifen and other ER therapeutics, and does not exhibit tamoxifen-like ER agonism in MCF7 cells. (In Vivo) :The pharmacokinetic profile of Brilanestrant (ARN-810) shows it is a olw clearance molecule across species, with good bioavailability (40%-60%) . Brilanestrant (ARN-810) (3 mg/kg, p.o.) shows substantial tumor-growth inhibition in a tamoxifen-sensitive MCF-7 xenograft model, while at the highest dose of 100 mg/kg/day, all animals show tumor regression of more than 50% without weight loss.Brilanestrant (ARN-810) exhibits low clearance (11 mL/min/kg) and 61% oral bioavailability. Brilanestrant (ARN-810) (1-100 mg/kg/day, p.o.) displays dose dependent efficacy in the MCF7 xenograft model.