AZD9496 (maleate)

AZD9496 maleate is a potent and selective estrogen receptor (ERα) antagonist with IC₅₀ of 0.28 nM. AZD9496 maleate is an orally bioavailable selective oestrogen receptor degrader (SERD). IC50 & Target: IC50: 0.28 nM (ERα antagonism), 0.14 nM (ERα downregulation), 0.82 nM (ERα binding)^[1] In Vitro: The potency of AZD9496 with IC₅₀ of 0.82 nM, 0.14 nM, and 0.28 nM in ERα binding, downregulation, and antagonism, respectively. AZD9496 significantly inhibits MCF-7 cell growth with EC₅₀ of 0.04 nM^[1]. Selectivity of AZD9496 over other tested nuclear hormone receptors is high: androgen receptor (AR), IC₅₀=30 μM; glucocorticoid receptor (GR), IC₅₀=9.2 μM; progesterone receptor (PR), IC₅₀=0.54 μM^[2]. In Vivo: Significant tumor growth inhibition is observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect is accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors lead to further growth-inhibitory effects compared with monotherapy alone. AZD9496, given once daily orally at 5 and 25 mg/kg produced statistically significant increases in uterine weight compared with the ICI 182780 control (P<0.001) but significantly lower than ICI 47699 (P=0.001)^[1]. AZD9496 is also tested in a long-term estrogen deprived model (LTED), using the HCC-1428 LTED cell line that grows in the absence of estrogen and is thought to best represent a model of aromatase inhibition. AZD9496 shows significant activity, with a dose of 5 mg/kg giving tumor regressions in this model^[2].