1639042-08-2

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