AZD 9496 is a potent and selective estrogen receptor downregulator (SERD) with an IC50 value of 0.138 nM for estrogen receptor α (ERα) downregulation. It is selective for ERα compared to other nuclear hormone receptors with IC50 values of 0.0008, 0.54, 9.2, and 30 μM for ERα, progesterone receptor (PR), glucocorticoid receptor (GR), and androgen receptor (AR), respectively. AZD 9496 decreases ERα activity (IC50 = 0.282 nM), measured via quantification of downstream PR activity, and reduces proliferation of MCF-7 breast cancer cells (IC50 = 0.0398 nM). It also inhibits MCF-7 xenograft growth in mice in a dose-dependent manner. AZD 9496 is orally bioavailable and formulations containing it are under investigation in clinical trials for treatment of ER positive breast cancer.
azd9496 was identified as a nonsteroidal small-molecule inhibitor of erα, which was a potent and selective antagonist and downregulator of erα. in addition, azd9496 could bind and downregulate clinically relevant esr1 mutants [1].
animal study reported that significant tumor growth inhibition was observed as low as 0.5 mg/kg dose of azd9496 in the estrogen-dependent mcf-7 xenograft model, and such effect was accompanied by a dose-dependent decrease in pr protein levels, providing potent antagonist activity. in addition, the combination of azd9496 with pi3k pathway and cdk4/6 inhibitors resulted in further growth-inhibitory effects when compared with monotherapy alone. furthermore, the tumor regression was also observed in a long-term estrogen-deprived breast model, in which significant erα protein downregulation was found [1].
0.82, 0.14 and 0.28 nm for erα binding, erα downregulation, erα antagonism, respectively
[1] weir hm et al. azd9496: an oral estrogen receptor inhibitor that blocks the growth of er-positive and esr1-mutant breast tumors in preclinical models. cancer res. 2016 jun 1;76(11):3307-18.
[2] https://clinicaltrials. gov/ct2/show/nct02780713 term=azd9496&rank=2
