GNE-149 is an orally bioavailable compound and full antagonist of estrogen receptor α (ERα) with an IC50 of 0.053 nM, classified as a selective estrogen receptor degrader (SERD), holding potential for breast cancer research.

ERα:0.053 nM (IC50)

GNE-149 demonstrates both antiproliferative activity and ERα degradation in MCF7 and T47D cells, achieving IC50 values of 0.66 and 0.69 nM for antiproliferation, and 0.053 and 0.031 nM for ERα degradation, respectively[1].

GNE-149 demonstrates significant in vivo efficacy across a range of doses (0.3-30 mg/kg) in MCF7 xenograft mouse models with either wild-type (WT) ERα or the Y537S mutant ERα variant, showing dose-dependent tumor regression in the latter at all doses above 0.3 mg/kg. Its pharmacokinetic profile is favorable, characterized by total clearance rates (CL) of 19 mL/min/kg in rats, 8 mL/min/kg in dogs, and 13 mL/min/kg in cynomolgus monkeys, along with oral bioavailability (F) rates of 31% in rats, 49% in dogs, and 28% in cynomolgus monkeys. This efficacy was observed in female Crl:NU Foxn1 nu mice, aged 7 weeks, orally administered with doses ranging from 0.3 to 30 mg/kg once daily (q.d.) for 21 days, resulting in tumor regression across observed doses in the WT and Y537S mutant MCF7 xenograft model.