IC50: 0.82, 0.14 and 0.28 nM for ERα binding, ERα downregulation, ERα antagonism, respectively
AZD9496 is an orally active estrogen receptor inhibitor.
Estrogen receptors (ERs) are a group of proteins presented inside and on cells, and they are receptors that are activated by the hormoneestrogen. ERs are found to be over-expressed in about 70% of breast cancer cases, referred to as "ER-positive".
In vitro: 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].
In vivo: 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].
Clinical trial: AZD9496 is currently being evaluated in a phase I clinical trial to assess the PK and safety of different forms and formulations [2].
References:
[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