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Purity: ≥98%
AZD9496 is a novel, potent, orally bioavailable, and selective estrogen receptor (ERα) downregulator and antagonist with an IC50 of 0.28 nM and a Ki of 0.7 nM. AZD9496 bound to both ERα and ERβ isoforms with pmol/L equipotent binding. AZD9496 specifically targets ERα in vitro to induce downregulation. Furthermore, it opposes and inhibits mutant ER both in vivo and in vitro. AZD9496 has IC50s of 0.82, 0.14, and 0.28 nM for ERα binding, ERα downregulation, and ERα antagonism, respectively. In vitro, AZD9496 bound and downregulated clinically significant ESR1 mutants, and in an ESR1-mutant patient-derived xenograft model with a D538G mutation, it prevented tumor growth. All things considered, the pharmacologic data demonstrated that AZD9496 is a selective estrogen receptor antagonist and downregulator in ER(+) breast cells that can be taken orally and is nonsteroidal. As such, it may be of significant assistance to patients with ER(+) breast cancer. A phase I clinical trial is evaluating AZD9496 at this time.
| Targets |
ERα antagonism (IC50 = 0.28 nM); ERα downregulation (IC50 = 0.14 nM); ERα binding (IC50 = 0.82 )
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| ln Vitro |
AZD9496 demonstrates potency in ERα binding, downregulation, and antagonism, with IC50 values of 0.82 nM, 0.14 nM, and 0.28 nM, respectively. With an EC50 of 0.04 nM, AZD9496 dramatically suppresses MCF-7 cell growth[1]. The study found that AZD9496 exhibits high selectivity towards the following tested nuclear hormone receptors: progesterone receptor (PR), IC50=0.54 μM; glucocorticoid receptor (GR), IC50=9.2 μM; androgen receptor (AR), IC50=30 μM[2].
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| ln Vivo |
In the estrogen-dependent MCF-7 xenograft model, significant inhibition of tumor growth is seen at doses as low as 0.5 mg/kg. This effect is accompanied by a dose-dependent reduction in PR protein levels, indicating an effective antagonist. Compared to monotherapy alone, AZD9496 combined with CDK4/6 inhibitors and the PI3K pathway has additional growth-inhibitory effects. When AZD9496 was taken orally once a day at doses of 5 and 25 mg/kg, it increased uterine weight statistically significantly (P<0.001) in comparison to the ICI 182780 control, but not as significantly as ICI 47699 (P=0.001)[1]. AZD9496 is also tested in a long-term estrogen-deprived model (LTED) with the HCC-1428 LTED cell line, which is considered the most accurate model of aromatase inhibition due to its ability to grow in the absence of estrogen. AZD9496 has a substantial impact; in this model, tumor regressions are seen at a dose of 5 mg/kg[2].
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| Enzyme Assay |
AZD9496 is a potent and orally bioavailable, selective antagonist and downregulator of the estrogen receptor (Ki=0.7 nM).
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| Cell Assay |
AZD9496, ICI 182780, and ICI 47699's effects on MCF-7 cells' ERα peptide turnover. Steroid-free conditions are maintained for the indicated duration of time, and cells are grown in SILAC media containing 13C615N4 L-arginine to label ERα peptide as "heavy" (blue line). Afterwards, the culture is switched to unlabeled L-arginine to label newly synthesized protein as "normal" (red line), with 0.1% DMSO, 300 nM Tamoxife, 100 nM AZD9496, or 100 nM ICI 182780. The displayed data is an average of two separate experiments [1].
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| Animal Protocol |
Mice: The effectiveness of AZD9496 in an MCF-7 xenograft model in vivo. PEG/captisol (vehicle) or AZD9496 (0.02, 0.1, 0.5, 10, and 50 mg/kg, p.o., q.d.) are the daily doses given to MCF-7 xenografts cultivated in male SCID mice. Every few months, the growth of the tumor is measured with a caliper, and the mean tumor volumes for every dose group are plotted.
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| References |
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| Molecular Formula |
C25H25F3N2O2
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| Molecular Weight |
442.47
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| Exact Mass |
442.19
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| Elemental Analysis |
C, 67.86; H, 5.70; F, 12.88; N, 6.33; O, 7.23
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| CAS # |
1639042-08-2
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| Related CAS # |
AZD9496 maleate;1639042-28-6
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| Appearance |
Solid powder
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| SMILES |
C[C@@H]1CC2=C([C@H](N1CC(C)(C)F)C3=C(C=C(C=C3F)/C=C/C(=O)O)F)NC4=CC=CC=C24
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| InChi Key |
DFBDRVGWBHBJNR-BBNFHIFMSA-N
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| InChi Code |
InChI=1S/C25H25F3N2O2/c1-14-10-17-16-6-4-5-7-20(16)29-23(17)24(30(14)13-25(2,3)28)22-18(26)11-15(12-19(22)27)8-9-21(31)32/h4-9,11-12,14,24,29H,10,13H2,1-3H3,(H,31,32)/b9-8+/t14-,24-/m1/s1
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| Chemical Name |
(E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1) .This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.65 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.65 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2600 mL | 11.3002 mL | 22.6004 mL | |
| 5 mM | 0.4520 mL | 2.2600 mL | 4.5201 mL | |
| 10 mM | 0.2260 mL | 1.1300 mL | 2.2600 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03236974 | Completed | Drug: Standard Arm - Fulvestrant Drug: AZD9496 |
Postmenopausal Women With ER+ HER2- Primary Breast Cancer |
AstraZeneca | October 5, 2017 | Phase 1 |
| NCT02248090 | Completed | Drug: AZD9496 | ER+ HER2- Advanced Breast Cancer |
AstraZeneca | October 22, 2014 | Phase 1 |
| NCT02780713 | Completed | Drug: AZD9496 (Reference) Drug: AZD9496 Variant A |
Breast Cancer | AstraZeneca | June 2, 2016 | Phase 1 |
 Crystal structure of the LBD of ERα in complex with AZD9496.Cancer Res. 2016 Jun 1;76(11):3307-18. |
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 Effect of AZD9496, fulvestrant, and tamoxifen on ERα peptide turnover in MCF-7 cells.Cancer Res. 2016 Jun 1;76(11):3307-18. |
 ERα-mediated agonism in MCF-7 cells and immature female rat endometrial tissue.Cancer Res. 2016 Jun 1;76(11):3307-18. |
In vivoefficacy of AZD9496 in MCF-7 xenograft model.Cancer Res. 2016 Jun 1;76(11):3307-18. |
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 Tumor regressions with AZD9496 in combination with mTOR, PIKC, and CDK4/6 inhibitors in MCF-7 xenograft model and in HCC1428 LTED model.Cancer Res. 2016 Jun 1;76(11):3307-18. |
AZD9496 is efficacious againstESR1mutantsin vitroandin vivo.Cancer Res. 2016 Jun 1;76(11):3307-18. |
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