| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| 10mg |
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| 50mg |
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| Other Sizes |
| Targets |
Neratinib irreversibly inhibits EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) by forming a covalent bond with Cys805/803 in the ATP-binding pocket, with IC50 values of ∼2-20 nM. Impurity 13 is a carboxylic acid degradation product where the acrylamide group (Michael acceptor) has been oxidized or hydrolyzed. This structural change eliminates covalent binding capability, greatly reducing inhibitory activity.
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|---|---|
| ln Vitro |
No in vitro kinase inhibition data are available for this impurity. Neratinib potently inhibits HER2 with IC50 ∼2 nM. Impurity 13, lacking the reactive acrylamide group, cannot form a covalent bond with the target cysteine residues. It would show only very weak reversible inhibition (IC50 >1 uM) if any. No specific cell-free kinase assays have been reported for this impurity.
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| ln Vivo |
No in vivo antitumor activity has been reported. Neratinib (240 mg/day) is effective in extending disease-free survival in HER2-positive breast cancer patients. Impurity 13 would have minimal activity in mouse xenograft models (e.g., BT474) even at high doses (100 mg/kg). It would not induce apoptosis or inhibit downstream MAPK/ERK and PI3K/AKT signaling pathways in vivo.
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| Enzyme Assay |
Non-cell characterization: ¹H NMR (400 MHz, DMSO-d₆) shows quinoline core protons, the 3-chloro-4-(pyridin-2-ylmethoxy)aniline group, and the oxoacetic acid COOH proton (delta ∼12.5 ppm, br s). LC-MS (ESI+) m/z 518.1 [M+H]+ (parent), with characteristic isotopic pattern for chlorine. HPLC-UV on a C18 column with mobile phase of 0.1% TFA in water/acetonitrile (gradient 20→70% B), detection 254 nm and 340 nm. Purity typically >95% by area normalization.
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| Cell Assay |
General cytotoxicity assay: BT474 or SK-BR-3 HER2-positive breast cancer cells (1×10⁴/well) are treated with impurity at concentrations of 0.01-10 uM for 72 h. Cell viability is measured by CellTiter-Glo. IC50 is expected to be >10 uM, much higher than for neratinib (IC50 ∼10-50 nM). No HER2 phosphorylation assays (Western blot for p-HER2 Tyr1248) are performed for an impurity.
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| Animal Protocol |
Animal toxicology study for impurity qualification: Sprague-Dawley rats (n=10/sex/group) receive oral impurity at 0.5, 2.5, 12.5 mg/kg/day for 28 days per ICH Q3B. Vehicle: 0.5% methylcellulose. Endpoints: body weight, food consumption, clinical signs, serum chemistry (ALT, AST, BUN, creatinine), hematology, and histopathology of liver, kidney, GI tract, and skin.
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| ADME/Pharmacokinetics |
No PK data are available for this impurity. Neratinib has an oral bioavailability of ∼40%, Tmax of 2-8 h, plasma protein binding of ∼99%, and a half-life of ∼7-17 h. Impurity 13, being a more polar carboxylic acid (MW 518, log P ∼2.5-3.0 vs. ∼3.5 for neratinib), would have lower oral absorption (<30%). t½ predicted ∼6-10 h. Metabolism via oxidation and conjugation. Excretion primarily fecal.
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| Toxicity/Toxicokinetics |
No toxicity data are available. In silico genotoxicity assessment (DEREK, Sarah) is required. The quinoline core generally has no structural alerts. An Ames test (TA98, TA100, TA1535, TA1537, WP2uvrA) with and without S9 is required for ICH M7 qualification. In a 28-day rat study, NOAEL expected at 2.5 mg/kg. No target-mediated diarrhea or skin rash is anticipated due to lack of HER2 inhibition.
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| Additional Infomation |
This impurity is also known as Neratinib Impurity 13 and Neratinib Carboxylic Acid Degradant. Storage at -20degC in a tightly sealed container, protected from light. Soluble in DMSO (≥5 mg/mL). Used for forced degradation studies under oxidative or hydrolytic stress conditions and stability-indicating HPLC method validation for neratinib maleate tablets.
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| Molecular Formula |
C26H20CLN5O5
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|---|---|
| Molecular Weight |
517.92
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| Exact Mass |
517.115
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| CAS # |
1144516-13-1
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| PubChem CID |
25267646
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
37
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| Complexity |
839
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC=CC=N4)Cl)C#N)NC(=O)C(=O)O
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| InChi Key |
LJBZJAUBLJREAU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H20ClN5O5/c1-2-36-23-11-20-18(10-21(23)32-25(33)26(34)35)24(15(12-28)13-30-20)31-16-6-7-22(19(27)9-16)37-14-17-5-3-4-8-29-17/h3-11,13H,2,14H2,1H3,(H,30,31)(H,32,33)(H,34,35)
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| Chemical Name |
2-[[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]amino]-2-oxoacetic acid
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9308 mL | 9.6540 mL | 19.3080 mL | |
| 5 mM | 0.3862 mL | 1.9308 mL | 3.8616 mL | |
| 10 mM | 0.1931 mL | 0.9654 mL | 1.9308 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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