AZD9496 maleate

Research use only, not for human use.

A potent, selective estrogen receptor downregulator (SERD) with ER downregulation pIC50 of 9.68.

A potent, selective estrogen receptor downregulator (SERD) with ER downregulation pIC50 of 9.68; shows pM equipotent binding to both ERα and ERβ isoforms, highly selective binding compared with progesterone (～650-fold), glucocorticoid (～11,223-fold), and androgen (～36,375-fold) receptor LBDs; downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer and orally available. Breast Cancer Phase 1 Clinical.

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. 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.

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). 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.

AZD-9496 maleate

Endocrinology/Hormones

Estrogen Receptor/ERR

Estrogen Receptor/ERR

Cancer

Breast Cancer

1639042-28-6

558.5456

C29H29F3N2O6

>98% (HPLC)

10 mM in DMSO

CC1CC2=C(C(N1CC(C)(C)F)C3=C(C=C(C=C3F)C=CC(=O)O)F)NC4=CC=CC=C24.C(=CC(=O)O)C(=O)O

2-Propenoic acid, 3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-2,3,4,9-tetrahydro-3-methyl-1H-pyrido[3,4-b]indol-1-yl]phenyl]-, (2E)-, (2Z)-2-butenedioate (1:1)

(-20℃)

With Ice Pack

≥ 2 years