AZ5104EGFR inhibitor CAS# 1421373-98-9 |
- AZ505 ditrifluoroacetate
Catalog No.:BCC4265
CAS No.:1035227-44-1
Quality Control & MSDS
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| Cas No. | 1421373-98-9 | SDF | Download SDF |
| PubChem ID | 71496460 | Appearance | Powder |
| Formula | C27H31N7O2 | M.Wt | 485.58 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 28 mg/mL (57.66 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide | ||
| SMILES | CN(C)CCN(C)C1=CC(=C(C=C1NC(=O)C=C)NC2=NC=CC(=N2)C3=CNC4=CC=CC=C43)OC | ||
| Standard InChIKey | IQNVEOMHJHBNHC-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C27H31N7O2/c1-6-26(35)30-22-15-23(25(36-5)16-24(22)34(4)14-13-33(2)3)32-27-28-12-11-21(31-27)19-17-29-20-10-8-7-9-18(19)20/h6-12,15-17,29H,1,13-14H2,2-5H3,(H,30,35)(H,28,31,32) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | AZ-5104 is an active, demethylated metabolite of AZD 9291. AZ-5104 is an EGFR inhibitor with IC50s of 1, 6, 1, 25 and 7 nM for EGFRL858R/T790M, EGFRL858R, EGFRL861Q, EGFR and ErbB4, respectively.In Vitro:AZ-5104 inhibits EGFR phosphorylation with IC50s of 2, 1, 2, 53, and 33 nM in H1975 (EGFRL858R/T790M), PC-9VanR (EGFRExon 19 deletion/T790M), PC-9 (EGFRExon 19 deletion), H2073 (WT), and LOVO (WT), respectively. AZ5104 exhibits a reduced selectivity margin against wild-type EGFR when compared to AZD9291. AZ5104 display minimal off-target activity against other non-HER family kinases, but has the potential to target both HER2 and HER4 kinase activity[1].In Vivo:The metabolite, AZ5104 (5 mg/kg/day), is effective in shrinking tumors in both C/L858R and C/L+T mice[1]. References: | |||||
AZ5104 Dilution Calculator
AZ5104 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.0594 mL | 10.297 mL | 20.5939 mL | 41.1879 mL | 51.4848 mL |
| 5 mM | 0.4119 mL | 2.0594 mL | 4.1188 mL | 8.2376 mL | 10.297 mL |
| 10 mM | 0.2059 mL | 1.0297 mL | 2.0594 mL | 4.1188 mL | 5.1485 mL |
| 50 mM | 0.0412 mL | 0.2059 mL | 0.4119 mL | 0.8238 mL | 1.0297 mL |
| 100 mM | 0.0206 mL | 0.103 mL | 0.2059 mL | 0.4119 mL | 0.5148 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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AZ5104, is the demethylated metabolite of AZD-9291,is a potent EGFR inhibitor. IC50 <1 nm, 6 1 25 for egfr (l858r>
EGFR (epidermal growth factor receptor) is a receptor tyrosine kinase on the cell surface. The receptor activation leads to dimerization and tyrosine autophosphorylation. It induces downstream cellular responses such as modification in gene expression, cell proliferation and cytoskeletal rearrangement etc.
Compare to AZD9291, AZ5104 has somewhat more potency in mutant EGFR cell lines ex19del (2 nmol/L in PC-9), T790M (2 nmol/L in H1975), and wild-type EGFR (33 nmol/L in LOVO) cell lines. In a phenotypic assay, AZ5104 showed a greater potency across cell lines in a phenotypic assay.
3 hours after oral dosing in the mouse, the circulating active metabolites in plasma is 33% for AZ5104. In both C/L858R and C/L+T mice, 5 mg/kg/day dose of AZ5104, also show efficacy in shrinking tumors.
Reference:
1. Cross DA, Ashton SE, Ghiorghiu S et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.
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Irreversible Inhibition of EGFR: Modeling the Combined Pharmacokinetic-Pharmacodynamic Relationship of Osimertinib and Its Active Metabolite AZ5104.[Pubmed:27439477]
Mol Cancer Ther. 2016 Oct;15(10):2378-2387.
Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines. Osimertinib was dosed in xenografted models of EGFR-driven cancers. In one set of experiments, changes in phosphorylated EGFR were measured to confirm target engagement. In a second set of efficacy studies, the resulting changes in tumor volume over time after repeat dosing of osimertinib were observed. To account for the contributions of both molecules, a mathematical modeling approach was taken to integrate the resulting datasets. The model was able to describe the pharmacokinetics, pharmacodynamics, and efficacy in A431, PC9, and NCI-H1975 xenografts, with the differences in sensitivity described by the varying potency against wild-type, sensitizing, and T790M-mutant EGFR and the phosphorylated EGFR reduction required to reduce tumor volume. It was inferred that recovery of pEGFR is slower after chronic dosing due to reduced resynthesis. It was predicted and further demonstrated that although inhibition is irreversible, the resynthesis of EGFR is such that infrequent intermittent dosing is not as efficacious as once daily dosing. Mol Cancer Ther; 15(10); 2378-87. (c)2016 AACR.
