ARN-509

ARN-509 is a selective and competitive androgen receptor inhibitor with IC50 of 16 nM in a cell-free assay, useful for prostate Y treatment. Phase 3. (In Vitro) :Apalutamide (ARN-509) also exhibits low micromolar affinity (IC50 3 μM) for the GABAA receptor in radioligand binding-assays and thus may potentially antagonize GABAA at therapeutic dose levels. Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. (In Vivo) :Apalutamide (ARN-509) exhibits low systemic clearance, high oral bioavailability and long plasma half-life in both mouse and dog, supporting once-daily oral dosing. Consistent with its long terminal-half-life, Apalutamide steady-state plasma-levels increases in repeat-dose studies, resulting in high C24hr levels and low peak:trough ratios (ratio:2.5) . Castrate male mice bearing LNCaP/AR xenograft tumors are treated with either Apalutamide at doses of 1, 10 or 30 mg/kg/day. Thirteen of 20 Apalutamide (30 mg/kg/day) -treated animals exhibit >50% reduction in tumor-volume at day 28 versus 3 of 19 MDV3100 (30 mg/kg/day) -treated mice.