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| 5mg |
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| 25mg |
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Purity: ≥98%
AEE788 (NVP-AEE-788; NVP-AEE788) is a novel, potent and orally bioavailable inhibitor of multiple receptor tyrosine kinase such as EGFR (epidermal growth factor receptor) and HER2/ErbB2 with potential antitumor activity. It has IC50 values of 2 nM and 6 nM for inhibiting EGFR and HER2/ErbB2, respectively. Its potency is lower against VEGFR2/KDR, c-Abl, c-Src, and Flt-1. No impacts on PKCα, CDK1, Ins-R, or IGF-1R. AEE788 prevents the tyrosine kinases of EGFR, HER2, and VEGF2 from becoming phosphorylated. This inhibits the proliferation of cells and induces the death of tumor cells and tumor-associated endothelial cells.
| Targets |
EGFR (IC50 = 2 nM); HER2/ErbB2 (IC50 = 6 nM); c-Abl (IC50 = 52 nM); FLT1 (IC50 = 59 nM); c-Fms (IC50 = 60 nM)
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
In vitro kinase assays are conducted using recombinant glutathione S-transferase-fused kinase domains (4-100 ng, depending on specific activity) in 96-well plates (30 μL) at room temperature for 15–45 minutes. The phosphate donor is polyGluTyr-(4:1) peptide, and the acceptor is [γ33P]ATP. Peptide substrates for cyclin-dependent kinase 1/cycB, protein kinase A, and all other kinases are protamine sulfate (200 μg/mL), histone H1 (100 μg/mL), and the heptapeptide Leu-Arg-Arg-Ala-Ser-Leu-Gly (also referred to as Kemptide Bachem). The following ATP concentrations are used in assays to maximize performance for each kinase: 10.0 μM (PDGFR-β, protein kinase C-α, and cyclin-dependent kinase 1), 2.0 μM (EGFR, erbB2, ErbB3, and ErbB4), 5.0 μM (c-abl), 8.0 μM (Flt-1, Flt-3, Flt-4, Flk, KDR, FGFR-1, and Tek), and 20.0 μM (c-Src and protein kinase A). The addition of 20 μL of 125 mM EDTA stops the reaction. The reaction mixture is transferred onto an Immobilon-polyvinylidene difluoride membrane containing thirty microliters (μL) for c-abl, c-Src, insulin-like growth factor-1R, RET-Men2A, and RET-Men2B, or forty μL for all other kinases. The membrane is then presoaked with 0.5% H3PO4 and mounted on a vacuum manifold. After applying vacuum, each is thoroughly rinsed with 200 μL of 0.5% H3PO4. Membranes are removed, and they are then cleaned once with ethanol and four times with 1.0% H3PO4. After mounting dried membranes in a Packard TopCount 96-well frame and adding 10 μL of Microscint per well, the membranes are counted. IC50 values (±SE) are averages of at least three determinations and are computed using linear regression analysis of the percentage inhibition.
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| Cell Assay |
The proliferation assay for methylene blue cells.96-well microtiter plates are seeded with 1.5 × 103 cells/well, and the cells are then incubated for an entire night at 37 °C, 5% v/v CO2, and 80% relative humidity. On day 1, dilutions of AEE788 are added, with 10 μM being the highest concentration. The cells are fixed with 3.3% v/v glutaraldehyde, rinsed with water, and stained with 0.05% w/v methylene blue after the cell plates are incubated for an additional 4 (T24) or 6 (BT-474, SK-BR-3, and NCI-H596) days. Following washing, 3% HCl is used to elute the dye, and a SpectraMax 340 spectrophotometer is used to measure the absorbance at 665 nm. The drug concentration that results in 50% inhibition of net cell mass increase when compared to untreated control cultures is known as the half-maximum concentration (IC50) value, which is calculated through mathematical curve-fitting.
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| Animal Protocol |
Mice: AEE788 is diluted in the ideal medium and in DMSO. For five days, BALB/c mice with s.c. A-431 squamous tumors (three animals per group) or HC11-NeuT-driven breast tumors (two animals per group) are given a daily oral dose of 30 mg/kg of AEE788 or a vehicle. The mice are given 500 μg EGF/kg body weight intravenously at different times after the compound treatment ends and before they are sacrificed. Alternatively, 0.2 ml 0.9% w/v NaCl is given as a vehicle control. The mice are killed and the tumors are removed five minutes after EGF administration.
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| References |
| Molecular Formula |
C27H32N6
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| Molecular Weight |
440.58
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| Exact Mass |
440.27
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| Elemental Analysis |
C, 73.60; H, 7.32; N, 19.07
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| CAS # |
497839-62-0
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CCN1CCN(CC1)CC2=CC=C(C=C2)C3=CC4=C(N3)N=CN=C4N[C@H](C)C5=CC=CC=C5
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| InChi Key |
OONFNUWBHFSNBT-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C27H32N6/c1-3-32-13-15-33(16-14-32)18-21-9-11-23(12-10-21)25-17-24-26(28-19-29-27(24)31-25)30-20(2)22-7-5-4-6-8-22/h4-12,17,19-20H,3,13-16,18H2,1-2H3,(H2,28,29,30,31)/t20-/m1/s1
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| Chemical Name |
6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
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| Synonyms |
NVP-AEE788; NVP-AEE-788; NVP-AEE 788; AEE 788; AEE-788; AEE788
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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 |
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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 (5.67 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 (5.67 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 (5.67 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: 30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2697 mL | 11.3487 mL | 22.6974 mL | |
| 5 mM | 0.4539 mL | 2.2697 mL | 4.5395 mL | |
| 10 mM | 0.2270 mL | 1.1349 mL | 2.2697 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 |
| NCT00107237 | Completed | Drug: AEE788 Drug: everolimus |
Brain and Central Nervous System Tumors |
Novartis Pharmaceuticals | October 2003 | Phase 1 Phase 2 |
| NCT00118456 | Completed | Drug: AEE788 | Cancer | Novartis Pharmaceuticals | July 2003 | Phase 1 |
| NCT00116376 | Completed | Drug: AEE788 | Glioblastoma Multiforme | Novartis Pharmaceuticals | January 2004 | Phase 1 Phase 2 |
Immunohistochemical analysis of human colon cancer surgical specimens for expression of TGF-α, EGF, EGFR, pEGFR, VEGF, VEGFR, pVEGFR, and CD31. Cancer Res. 2005 May 1;65(9):3716-25. |
Double-immunofluorescence staining for expression of EGFR, pEGFR, VEGFR, or pVEGFR in tumor-associated endothelial cells. Cancer Res. 2005 May 1;65(9):3716-25. |
Analysis for cell proliferation, apoptosis, and microvessel density. A, mice were treated with saline (control), AEE788, CPT-11, or the combination of AEE788 and CPT-11. Cecal tumors were excised and processed for immunohistochemical analysis. B, double-immunofluorescence staining of CD31/PECAM-1 and TUNEL (apoptosis) tumors from mice treated with the combination of AEE788 and CPT-11. Cancer Res. 2005 May 1;65(9):3716-25. |
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