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Camizestrant (AZD-9833; compound 28) is a novel, highly potent and orally bioavailable SERD (Selective Estrogen Receptor Degrader) and ER Antagonist. AZD-9833 is used for the study of ER+ HER2-advanced breast cancer. AZD-9833 was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that AZD-9833 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration.
Camizestrant (AZD9833) is a next-generation, orally bioavailable selective estrogen receptor degrader (SERD) and complete estrogen receptor antagonist developed for the treatment of estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer . It functions by binding to the estrogen receptor and inducing a conformational change that leads to its proteasome-mediated degradation, thereby preventing ER-driven cancer cell growth and overcoming key endocrine resistance mechanisms, including ESR1 mutations . In the pivotal Phase III SERENA-6 trial, switching patients with an emerging ESR1 mutation to camizestrant plus a CDK4/6 inhibitor reduced the risk of disease progression or death by 56% compared to continuing standard-of-care treatment (median progression-free survival: 16.0 vs. 9.2 months; HR 0.44) . The safety profile is characterized by low-grade, reversible visual effects (photopsia) and bradycardia, with a pharmacokinetic profile supporting once-daily dosing (half-life: 20-23 hours) . It is currently being evaluated in multiple Phase III trials, including the adjuvant CAMBRIA-1 and CAMBRIA-2 studies for early breast cancer, and has received Breakthrough Therapy Designation from the U.S. FDA .| Targets |
Estrogen receptor α (ERα).
Camizestrant (AZD9833) functions as a selective estrogen receptor degrader (SERD) and antagonist. It binds to ERα and induces its degradation. [1] Based on the nonclinical electroretinogram (ERG) findings, the visual effects observed are not mediated by ERα, as other ER degraders/modulators are not associated with similar visual effects. The mechanism underlying the retinal effects is unclear but may involve a direct or indirect effect on bipolar, amacrine, or horizontal cells of the retina. [2] |
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| ln Vitro |
Camizestrant (compound 28) is a highly potent SERD. It demonstrates potent ER binding affinity (pIC50 = 8.6) and potent ER degradation activity in a cellular assay (pIC50 = 9.8) with a maximum degradation (Dmax) of 99% relative to fulvestrant in MCF-7 cells. [1]
It shows concentration-dependent decrease in ERα expression in MCF-7 cells (pIC50 = 9.8) and no evidence of ERα agonism as measured by progesterone receptor (PR) expression (pIC50 < 6.5). [1] No change in ERα downregulation potency was observed in the presence of the protein synthesis inhibitor cycloheximide (pIC50 = 9.9), while an expected decrease in potency was observed when treated with tamoxifen (pIC50 = 8.2) due to competition at the ERα ligand binding site. [1] Unlike estradiol, camizestrant does not increase the expression of ERα target genes PGR, TFF1, and GREB1; instead, it significantly reduces TFF1 and GREB1 expression, consistent with an SERD mode of action. [1] In a PR immunofluorescence assay, camizestrant potently and completely inhibits estradiol-induced PR expression in MCF-7 (wild-type) cells and blocks constitutive PR expression in MCF-7 (Y537S mutant) cells. [1] By Western blot analysis, camizestrant is a potent degrader of ERα with a profile very similar to fulvestrant in both MCF-7 and CAMA-1 cell lines. [1] It shows concentration-dependent inhibition of estradiol-driven cell growth in wild-type MCF-7 cells, with a slightly decreased potency in the MCF-7 (Y537S) mutant cell line. [1] Camizestrant is highly soluble in aqueous media (833 μM) and has good intrinsic cellular permeability (Papp = 13 × 10⁻⁶ cm/s) as measured in a Caco-2 assay. [1] In a panel of in vitro safety assays, camizestrant demonstrates excellent selectivity against a diverse range of off-target or secondary pharmacology targets, including 195 diverse enzyme, membrane transporter, GPCR, kinase, nuclear hormone receptor, and ion channel targets. Only one target, histamine H3 (antagonist), showed activity (IC50 = 0.33 μM). [1] |
| ln Vivo |
In an MCF-7 xenograft model in male SCID mice supplemented with an estradiol pellet, camizestrant (AZD9833) causes a dose-dependent decrease in tumor volume. At a dose of 2 mg/kg daily, it causes 73% tumor growth inhibition. At doses of 10 mg/kg and 50 mg/kg daily, it causes 15% and 53% tumor regressions, respectively. Treatment with 10 mg/kg and 50 mg/kg also causes a statistically significant reduction in PR expression in tumors (to 8.9% and 6.3% of vehicle control, respectively). Both doses gave greater antitumor and pharmacodynamic effects than 5 mg of fulvestrant dosed three times a week. [1]
In a nonclinical rat model, following 7 consecutive days of oral administration, camizestrant at doses ≥ 12 mg/kg/day significantly alters retinal responses as measured by electroretinograms (ERGs). The effects are dose-dependent, reversible (returning to baseline after a 7-day washout), and occur in the absence of any structural changes in the eye. [2] In human parental MCF7 mice xenografts, camizestrant (oral; 0.2–50 mg/kg; 20 days) demonstrates dose-dependent antitumor effectiveness [3]. Tumor growth is reduced by camistrant (oral; 0.8–40 mg/kg; 30 days) in a dose-dependent manner. At doses more than 10 mg/kg, it virtually totally prevents tumor growth in mice [3]. |
| Enzyme Assay |
ER Binding Assay: The binding affinity of camizestrant (compound 28) to ERα was determined in a competitive radioligand binding assay. The compound showed potent binding with a pIC50 of 8.6 (n ≥ 2, SEM within 0.2 units). [1]
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| Cell Assay |
ER Binding Assay: The binding affinity of camizestrant (compound 28) to ERα was determined in a competitive radioligand binding assay. The compound showed potent binding with a pIC50 of 8.6 (n ≥ 2, SEM within 0.2 units). [1]
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| Animal Protocol |
MCF-7 Xenograft Model (Mouse): MCF-7 cells were injected into male SCID mice supplemented with an estradiol pellet. Once tumors reached ~300 mm³, mice were randomized into groups and treated with vehicle control or daily doses of camizestrant (0.5, 2, 10, or 50 mg/kg) or 5 mg of fulvestrant three times a week for 21 days. The compound was formulated in 5% DMSO / 95% hydroxypropyl β-cyclodextrin (30% w/v) for oral administration. Tumor volumes were measured twice a week. Twenty-four hours after the last dose, tumors were collected for analysis of PR expression by Western blot. [1]
Electroretinogram (ERG) Study in Rats: Female Long Evans rats received once-daily oral doses of camizestrant (5, 12, 25, or 75 mg/kg/day) or control for 7 consecutive days. The compound was formulated in deionized purified water pH-adjusted to 4.8–5.5. Animals were observed for an additional 7 days without further dosing. Full-field ERGs were recorded once during the pre-dose phase (baseline), at approximately 90 minutes post-dose on Days 1 and 7, and 7 days after the last dose (Day 14). Ophthalmic examinations were conducted pre-dose and on Days 8 and 15. [2] Mass Spectrometry Imaging (MSI) Study in Rats: A separate group of rats received daily oral doses of camizestrant (75 mg/kg/day) or control for 7 days. Animals were euthanized 2 hours post-dose on Day 7, and eyes were collected for mass spectrometry imaging to assess the retinal distribution of the compound. [2] Animal/Disease Models: Human ESR1 mutated breast cancer patient-derived female NSG mouse CTC174 cell xenograft [3] Doses: 0.8 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kg given Medication: Oral administration; 30 days; one time/day. Experimental Results: Inhibited tumor growth in a dose-dependent manner. |
| ADME/Pharmacokinetics |
Camizestrant (AZD9833) shows high solubility in aqueous media (833 μM) and good intrinsic permeability (Papp = 13 × 10⁻⁶ cm/s) in Caco-2 cells, predicting high fraction absorbed in humans. [1]
In rats, camizestrant (28) has moderate to high in vitro clearance in hepatocytes (23 μL/min/10⁶ cells) and high in vivo clearance (73 mL/min/kg), with a volume of distribution (Vd) of 13 L/kg and a half-life (t1/2) of 3.0 h. Oral bioavailability (%F) in rats is 19%. [1] In mice, camizestrant (28) has moderate to high in vitro clearance in hepatocytes (18 μL/min/10⁶ cells) and high in vivo clearance (59 mL/min/kg), with a volume of distribution (Vd) of 9.2 L/kg and a half-life (t1/2) of 5.1 h. Oral bioavailability (%F) in mice is 16%. [1] In the nonclinical rat ERG study, plasma concentrations of camizestrant showed dose-proportional exposure. Mean unbound plasma concentrations on Day 1 were 1590, 694, 199, and 46 nmol/L for doses of 75, 25, 12, and 5 mg/kg/day, respectively. On Day 7, mean unbound plasma concentrations were 1570, 560, 188, and 52 nmol/L for the same respective doses. [2] In humans, the unbound maximum concentration (Cmax) at the 75 mg once-daily clinical dose is a geometric mean of 0.034 μM (34 nmol/L). [2] Mass spectrometry imaging in rats showed that camizestrant accumulates primarily in the choroid and retinal pigment epithelium (RPE) following 7 days of oral administration at 75 mg/kg/day. [2] |
| Toxicity/Toxicokinetics |
Camizestrant (AZD9833) shows high solubility in aqueous media (833 μM) and good intrinsic permeability (Papp = 13 × 10⁻⁶ cm/s) in Caco-2 cells, predicting high fraction absorbed in humans. [1]
In rats, camizestrant (28) has moderate to high in vitro clearance in hepatocytes (23 μL/min/10⁶ cells) and high in vivo clearance (73 mL/min/kg), with a volume of distribution (Vd) of 13 L/kg and a half-life (t1/2) of 3.0 h. Oral bioavailability (%F) in rats is 19%. [1] In mice, camizestrant (28) has moderate to high in vitro clearance in hepatocytes (18 μL/min/10⁶ cells) and high in vivo clearance (59 mL/min/kg), with a volume of distribution (Vd) of 9.2 L/kg and a half-life (t1/2) of 5.1 h. Oral bioavailability (%F) in mice is 16%. [1] In the nonclinical rat ERG study, plasma concentrations of camizestrant showed dose-proportional exposure. Mean unbound plasma concentrations on Day 1 were 1590, 694, 199, and 46 nmol/L for doses of 75, 25, 12, and 5 mg/kg/day, respectively. On Day 7, mean unbound plasma concentrations were 1570, 560, 188, and 52 nmol/L for the same respective doses. [2] In humans, the unbound maximum concentration (Cmax) at the 75 mg once-daily clinical dose is a geometric mean of 0.034 μM (34 nmol/L). [2] Mass spectrometry imaging in rats showed that camizestrant accumulates primarily in the choroid and retinal pigment epithelium (RPE) following 7 days of oral administration at 75 mg/kg/day. [2] |
| References |
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| Additional Infomation |
Camizestrant is an orally administered selective estrogen receptor degrader (SERD) with potential antitumor activity. Upon administration, carizestrant binds to the estrogen receptor (ER), inducing a conformational change that leads to receptor degradation. This blocks ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells.
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| Molecular Formula |
C24H28F4N6
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|---|---|
| Molecular Weight |
476.512938499451
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| Exact Mass |
476.231
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| CAS # |
2222844-89-3
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| PubChem CID |
134453496
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
674
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC(CN1[C@H](C)CC2C3C=NNC=3C=CC=2[C@H]1C1C=CC(=CN=1)NC1CN(CCCF)C1)(F)F
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| InChi Key |
WDHOIABIERMLGY-CMJOXMDJSA-N
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| InChi Code |
InChI=1S/C24H28F4N6/c1-15-9-19-18(4-6-21-20(19)11-30-32-21)23(34(15)14-24(26,27)28)22-5-3-16(10-29-22)31-17-12-33(13-17)8-2-7-25/h3-6,10-11,15,17,23,31H,2,7-9,12-14H2,1H3,(H,30,32)/t15-,23+/m1/s1
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| Chemical Name |
N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine
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| Synonyms |
AZD9833; AZD-9833; Camizestrant; 2222844-89-3; JUP57A8EPZ; AZD 9833
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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 |
| 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) |
DMSO : ~100 mg/mL (~209.86 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.5 mg/mL (15.74 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 75.0 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: 7.5 mg/mL (15.74 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 75.0 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. View More
Solubility in Formulation 3: ≥ 7.5 mg/mL (15.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2.5 mg/mL (5.25 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: 2.5 mg/mL (5.25 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0986 mL | 10.4930 mL | 20.9859 mL | |
| 5 mM | 0.4197 mL | 2.0986 mL | 4.1972 mL | |
| 10 mM | 0.2099 mL | 1.0493 mL | 2.0986 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.
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