AZD9496 maleate is a highly potent and selective antagonist of the estrogen receptor alpha (ERα), exhibiting an IC50 value of 0.28 nM. This compound, AZD9496 maleate, is an orally bioavailable selective estrogen receptor degrader (SERD).

ERα downregulation:0.14 nM (IC50), ERα antagonism:0.28 nM (IC50), ERα binding:0.82 nM (IC50)

AZD9496 demonstrates significant efficacy in estrogen receptor alpha (ERα) interactions, exhibiting IC50 values of 0.82 nM for ERα binding, 0.14 nM for downregulation, and 0.28 nM for antagonism. It notably inhibits MCF-7 cell proliferation, with an EC50 value of 0.04 nM[1]. Furthermore, AZD9496 possesses high selectivity over other nuclear hormone receptors, with IC50 values indicating much weaker interaction with the androgen receptor (AR) at 30 μM, the glucocorticoid receptor (GR) at 9.2 μM, and the progesterone receptor (PR) at 0.54 μM[2].

In the estrogen-dependent MCF-7 xenograft model, noticeable tumor suppression was observed with doses as low as 0.5 mg/kg. This suppression coincided with a dose-responsive reduction in PR protein levels, indicating strong antagonist properties. Enhanced inhibitory effects on tumor growth were observed when AZD9496 was combined with PI3K pathway and CDK4/6 inhibitors, surpassing the outcomes seen with monotherapy. Administered orally once daily, AZD9496 doses of 5 and 25 mg/kg significantly increased uterine weight compared to the control ICI 182780 (P<0.001), though to a lesser extent than ICI 47699 (P=0.001). Additionally, AZD9496's effectiveness was evaluated in the long-term estrogen deprived (LTED) model using the HCC-1428 LTED cell line, which proliferates in the absence of estrogen, simulating an aromatase inhibition scenario. Here, a dosage of 5 mg/kg resulted in tumor regression, showcasing the compound's significant efficacy in this model.