| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
|
Purity: ≥98%
AZ5104 (AZ-5104), a demethylated and active metabolite of Osimertinib (AZD-9291), is an irreversible EGFR inhibitor with potential antitumor activity. Its IC50 values are 1, 6, 1, 25, and 7 nM for EGFRL858R/T790M, EGFRL858R, EGFRL861Q, EGFR, and ErbB4 inhibition, respectively. A novel and selective third-generation irreversible inhibitor, AZD9291 spares wild-type EGFR while inhibiting both EGFRm(+) sensitizing and T790M resistance mutants.
| Targets |
EGFRL858R/T790M (IC50 = 1 nM); EGFRL858R (IC50 = 1 nM); EGFRL861Q (IC50 = 6 nM); EGFR (IC50 = 25 nM); ErbB4 (IC50 = 7 nM); EGFRExon 19 deletion/T790M
|
|---|---|
| ln Vitro |
Motesanib exhibits >1000 selectivity against EGFR, Src, and p38 kinase in addition to having broad activity against the human VEGFR family. With an IC50 of 10 nM, motesanib dramatically suppresses HUVECs' VEGF-induced cellular proliferation, but has minimal effect on bFGF-induced proliferation (IC50 of >3,000 nM). With an IC50 of 207 nM for PDGF-induced proliferation and 37 nM for SCF-induced c-kit phosphorylation, respectively, motesanib also potently inhibits these processes[1]. However, it is ineffective against EGF-induced EGFR phosphorylation and A431 cell viability. Despite having minimal effect on HUVECs' ability to proliferate, motesanib treatment greatly increases the cells' sensitivity to fractionated radiation[2].
|
| ln Vivo |
Motesanib (100 mg/kg) significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. In the rat corneal model, oral Motesanib administration twice daily or once daily (ED50 = 2.1 mg/kg and 4.9 mg/kg, respectively) potently inhibits VEGF-induced angiogenesis in a dose-dependent manner. Through the selective targeting of tumor cell neovascularization, motesanib causes a dose-dependent tumor regression in established A431 xenografts[1]. In xenograft models of head and neck squamous cell carcinoma (HNSCC), motesanib in combination with radiation exhibits strong anti-tumor activity(2]. Blood vessel density and tumor growth of MCF-7, MDA-MB-231, or Cal-51 xenografts are also significantly reduced by metecanib treatment in a dose-dependent manner. These effects can be further amplified in combination with tamoxifen or docetaxel[3].
|
| Enzyme Assay |
Homogeneous time-resolved fluorescence (HTRF) assays are used to determine suitable enzyme, ATP, and substrate (gastrin peptide) concentrations for each enzyme. Using a two-thirds Km ATP concentration for each enzyme, motesanib is tested in a 10-point dose-response curve. An enzyme is combined with kinase reaction buffer (20 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 5 mM MnCl2, 100 mM NaCl, 1.5 mM EGTA) in the majority of assays. Prior to each experiment, a final concentration of 20 μg/mL BSA, 0.2 mM NaVO4, and 1 mM DTT is added. The HTRF reaction is preceded in all assays by the addition of 0.1125 nM Eu-PT66 and 5.75 mg/mL streptavidin-allophycocyanin. Using a Discovery instrument, plates are read after 30 minutes of room temperature incubation. Levenberg-Marquardt algorithm is used to calculate IC50 values, which are then entered into a four-parameter logistic equation.
|
| Cell Assay |
After exposing the cells to either 50 ng/mL VEGF or 20 ng/mL bFGF for an extra 72 hours, the cells are preincubated for two hours at varying concentrations of motesanib. Plates are frozen for 24 hours at -70°C after cells are twice cleaned with DPBS. Plates are read using a Victor 1420 workstation, and proliferation is measured by adding CyQuant dye. The four-parameter logistic equation is derived from the IC50 data using the Levenberg-Marquardt algorithm.
|
| Animal Protocol |
Penicillin/streptomycin/glutamine, 10% FBS, and DMEM (low glucose) are used to cultivate A431 cells. After trypsinization, the cells are collected and diluted to a 5×107/mL concentration in serum-free medium. The animals are given 1x107 cells in 0.2 mL over their left flank as a challenge. Ten days later, mice are treated with either vehicle (Ora-Plus) or motesanib, randomly assigned based on initial tumor volume measurements. Body weights and tumor volumes are noted on the day of sacrifice as well as twice a week. A Pro-Max electronic digital caliper is used to measure tumor volume, which is then computed using the formula length (mm)×width (mm)×height (mm) and expressed in mm3. The expression of data is mean±SE. Repeated actions ANOVA is used to assess the statistical significance of observed differences, with Scheffe post hoc testing for multiple comparisons used afterwards.
|
| References |
|
| Molecular Formula |
C27H31N7O2
|
|---|---|
| Molecular Weight |
485.5807
|
| Exact Mass |
485.25
|
| Elemental Analysis |
C, 66.78; H, 6.43; N, 20.19; O, 6.59
|
| CAS # |
1421373-98-9
|
| Related CAS # |
AZ-5104-d2;2719691-01-5
|
| Appearance |
Solid powder
|
| SMILES |
CN(C)CCN(C)C1=CC(=C(C=C1NC(=O)C=C)NC2=NC=CC(=N2)C3=CNC4=CC=CC=C43)OC
|
| InChi Key |
IQNVEOMHJHBNHC-UHFFFAOYSA-N
|
| InChi Code |
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)
|
| Chemical Name |
N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide
|
| Synonyms |
Demethylated AZ9291; active metabolite of AZD9291 (Osimertinib); AZ5104; AZ-5104;
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO: ~97 mg/mL (~199.8 mM)
Ethanol: ~5 mg/mL (~10.3 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.15 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 (5.15 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.15 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: 1% Tween 80:30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0594 mL | 10.2970 mL | 20.5939 mL | |
| 5 mM | 0.4119 mL | 2.0594 mL | 4.1188 mL | |
| 10 mM | 0.2059 mL | 1.0297 mL | 2.0594 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.
 AZD9291 binding mode and structure.Cancer Discov.2014 Sep;4(9):1046-61. |
|---|
 Effect of AZD9291 on EGFR phosphorylationin vitro.Cancer Discov.2014 Sep;4(9):1046-61. |
 In vivoanti-tumor efficacy of AZD9291 in subcutaneous xenograft models of EGFR-TKI sensitising and T790M resistant lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
 AZD9291 induces significant and sustained tumor regression in transgenic models of EGFR-TKI sensitising (C/L858R) and T790M resistant (C/L+T) lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
|---|
 AZD9291 inhibits EGFR phosphorylation and downstream signallng in murine models of EGFR T790M resistant lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
 Proof of concept clinical studies validating AZD9291 as a mutant-selective EGFR kinase T790M inhibitor.Cancer Discov.2014 Sep;4(9):1046-61. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA