Neratinib (HKI-272; PB272; Nerlynx)

Alias: Neratinib; HKI-272; PB272; HKI272; PB 272; HKI 272; PB-272; trade name: Nerlynx
Cat No.:V0537 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.
Neratinib (HKI-272; PB272; Nerlynx) Chemical Structure CAS No.: 698387-09-6
Product category: EGFR
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
5mg
25mg
50mg
100mg
250mg
500mg
1g
Other Sizes

Other Forms of Neratinib (HKI-272; PB272; Nerlynx):

  • NERATINIB MALEATE
  • Neratinib-d6 (neratinib d6)
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
Targets
HER2 (IC50 = 59 nM); EGFR (IC50 = 92 nM); KDR (IC50 = 800 nM); Src (IC50 = 1.4 μM)
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].
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%.
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%.
Animal Protocol
Female athymic (nude) mice, tumor xenograft[1]
10, 20, 40, 60 or 80 mg/kg/day
Gavage, 42 days
References

[1]. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res, 2004, 64(11), 3958-3965.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C30H29CLN6O3
Molecular Weight
557.04
Exact Mass
556.20
Elemental Analysis
C, 64.68; H, 5.25; Cl, 6.36; N, 15.09; O, 8.62
CAS #
698387-09-6
Appearance
Solid powder
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
InChi Key
JWNPDZNEKVCWMY-VQHVLOKHSA-N
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+
Chemical Name
(E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
Synonyms
Neratinib; HKI-272; PB272; HKI272; PB 272; HKI 272; PB-272; trade name: Nerlynx
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 Data
Solubility (In Vitro)
DMSO: 3~12 mg/mL (vary from batch to batch)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
30% PEG400+0.5% Tween80+5% propylene glycol: 5 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
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.

Calculator

Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?
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  • The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
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g/mol

Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Definitions of molecular mass, molecular weight, molar mass and molar weight:
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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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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.

Clinical Trial Information
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
Biological Data
  • Neratinib (HKI-272)

    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.

  • Neratinib (HKI-272)

    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.

  • Neratinib (HKI-272)

    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.

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