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5mg |
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25mg |
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50mg |
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100mg |
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250mg |
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500mg |
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1g |
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Purity: ≥98%
Neratinib (formerly known as HKI-272 or PB-272; trade name: Nerlynx) is a highly potent, selective, and orally bioavailable HER2 and EGFR inhibitor with potential antitumor activity. In cell-free assays, it inhibits HER2 and EGFR with IC50s of 59 nM and 92 nM, respectively. The FDA gave it approval in 2017 to treat breast cancer. Neratinib exhibits no discernible inhibition of Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf, and c-Met, and it only weakly inhibits KDR and Src.
Targets |
HER2 (IC50 = 59 nM); EGFR (IC50 = 92 nM); KDR (IC50 = 800 nM); Src (IC50 = 1.4 μM)
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ln Vitro |
Neratinib shows no action against tyrosine kinase c-Met[1], Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, among other serine-threonine kinases[1].
Neratinib is much less active in cell lines that express neither EGFR nor HER-2 (3T3, MDA-MB-435, and SW620), and it inhibits the proliferation of cell lines that exhibit high levels of HER-2 (3T3/neu, SK-Br-3, and BT474)[1]. Neratinib (0-2 nM, 12-16 h) arrests BT474 cell cycle at G1-S phase[1]. Neratinib causes cyclin D1 levels to be down-regulated, Akt and MAPK phosphorylation to be inhibited, and p27 to be induced[1]. |
ln Vivo |
Neratinib (HKI-272) exhibits anticancer properties against cancer cells that express high levels of EGFR or HER-2 (0-80 mg/kg/day; i.e., 42 days)[1].
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Enzyme Assay |
Prepared as 10 mg/mL stocks in DMSO, neratinib is diluted in 25 mM HEPES (pH 7.5; 0.002 ng/mL–20 μg/mL). In 96-well ELISA plates, purified recombinant COOH-terminal fragments of HER2 (amino acids 676-1255) or epidermal growth factor receptor (EGFR) (amino acids 645-1186) are diluted in 100 mM HEPES (pH 7.5) and 50% glycerol. The mixture is then incubated with increasing concentrations of Neratinib in 4 mM HEPES (pH 7.5), 0.4 mM MnCl2, 20 μM sodium vanadate, and 0.2 mM DTT for 15 minutes at room temperature. 40 μM ATP and 20 mM MgCl2 are added to start the kinase reaction, which is then left to run at room temperature for an hour. Wash the plates, then use anti-phospho-tyrosine antibodies (15 ng/well) labeled with europium to detect phosphorylation. Using a Victor2 fluorescence reader (excitation wavelength of 340 nm and emission wavelength of 615 nm), the signal is detected following the washing and enhancement stages. An inhibition curve is used to determine the concentration of Neratinib (IC50) at which receptor phosphorylation is inhibited by 50%.
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Cell Assay |
Different concentrations of Neratinib are applied to cells (3T3, 3T3/neu, A431, BT474, SK-Br-3, MDA-MB-435, and SW480) for a period of either two or six days. A protein-binding dye called sulforhodamine B is used to measure cell proliferation. In short, cells are thoroughly cleaned with water after being fixed with 10% trichloroacetic acid. After staining the cells with 0.1% sulforhodamine B, they are rinsed in 5% acetic acid. After solubilizing the protein-associated dye in 10 mM Tris, the absorbance is calculated at 450 nM. Inhibition curves are used to calculate the concentration of neratinib (IC50) that inhibits cell proliferation by 50%.
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Animal Protocol |
Female athymic (nude) mice, tumor xenograft[1]
10, 20, 40, 60 or 80 mg/kg/day Gavage, 42 days |
References |
Molecular Formula |
C30H29CLN6O3
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Molecular Weight |
557.04
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Exact Mass |
556.20
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Elemental Analysis |
C, 64.68; H, 5.25; Cl, 6.36; N, 15.09; O, 8.62
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CAS # |
698387-09-6
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Appearance |
Solid powder
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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=C/CN(C)C
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InChi Key |
JWNPDZNEKVCWMY-VQHVLOKHSA-N
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InChi Code |
InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+
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Chemical Name |
(E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
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Synonyms |
Neratinib; HKI-272; PB272; HKI272; PB 272; HKI 272; PB-272; trade name: Nerlynx
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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) |
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Solubility (In Vivo) |
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Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.7952 mL | 8.9760 mL | 17.9520 mL | |
5 mM | 0.3590 mL | 1.7952 mL | 3.5904 mL | |
10 mM | 0.1795 mL | 0.8976 mL | 1.7952 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 |
NCT05154396 | Not yet recruiting | Drug: Neratinib | HER2-positive Breast Cancer | Chinese Academy of Medical Sciences |
January 1, 2022 | Phase 2 |
NCT05388149 | Recruiting | Drug: Neratinib | Breast Cancer HER2-positive Breast Cancer |
University Health Network, Toronto |
December 6, 2022 | Phase 2 |
NCT02932280 | Recruiting | Drug: Neratinib | Solid Tumor Lymphoma |
Memorial Sloan Kettering Cancer Center |
October 2016 | Phase 1 Phase 2 |
NCT06083662 | Active Recruiting |
Drug: Neratinib Maleate | Metastatic Cancer HER2 Gene Mutation |
Korea University Guro Hospital | June 15, 2021 | Phase 2 |
NCT03457896 | Active Recruiting |
Drug: Neratinib Drug: Cetuximab |
Metastatic Colorectal Cancer | NSABP Foundation Inc | May 18, 2018 | Phase 2 |
Effect of HKI-272 on cell cycle regulatory proteins. BT474 cells were incubated with HKI-272 for 12–16 h at 37°C. Protein extracts were analyzed by immunoblotting using cyclin D1, p27, or retinoblastoma (Rb)-specific antibodies. Actin antibodies were used as control. Cancer Res. 2004 Jun 1;64(11):3958-65. td> |
In vivo activity of HKI-272. A, groups of 10 mice were implanted with 2 × 106 3T3/neu cells. Animals were treated with the vehicle or HKI-272 on days 1–10 (p.o.), beginning the day after implantation. B–E, mice were implanted with BT474 tumor fragments (30 mm3; B), 5 × 106 SK-OV-3 cells (C), 5 × 106 A431 cells (D), or MCF-7 tumor fragments (30 mm3; E). Cancer Res. 2004 Jun 1;64(11):3958-65. td> |
Inhibition of HER-2 phosphorylation in xenografts. BT474 tumor-bearing mice (5 animals/group) were treated with vehicle or a single dose of HKI-272. Tumors from control and treated mice were dissected at various times after compound administration. Cancer Res. 2004 Jun 1;64(11):3958-65. td> |