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    Neratinib (HKI-272; PB272; Nerlynx)
    Neratinib (HKI-272; PB272; Nerlynx)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0537
    CAS #: 698387-09-6Purity ≥98%

    Description: Neratinib (formerly known as HKI-272 or PB-272; trade name: Nerlynx) is a highly potent, selective, and orally available HER2 and EGFR inhibitor with potential antitumor activity. It inhibits HER2 and EGFR with IC50s of 59 nM and 92 nM in cell-free assays. It was approved by FDA  in 2017 to treat breast cancer. Neratinib weakly inhibits KDR and Src, and it shows no significant inhibition to Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. 

    References: Cancer Res. 2004 Jun 1;64(11):3958-65.

    Related CAS: 915942-22-2 (maleate); 698387-09-6 (free base) 

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    Molecular Weight (MW)557.04
    FormulaC30H29ClN6O3
    CAS No.698387-09-6 (free); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 5 mg/mL (9.0 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 5 mg/mL
    SynonymsNeratinib; HKI-272; PB272; HKI272; HKI 272; PB 272; PB-272; trade name: Nerlynx

    Chemical Name: (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide

    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+

    SMILES Code: O=C(NC1=C(OCC)C=C2N=CC(C#N)=C(NC3=CC=C(OCC4=NC=CC=C4)C(Cl)=C3)C2=C1)/C=C/CN(C)C



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    In Vitro

    In vitro activity: Neratinib weakly inhibits tyrosine kinases KDR and Src with IC50 of 0.8 μM and 1.4 μM, respectively, being 14- and 24-fold less active compared with HER2. Neratinib displays no activity against other serine-threonine kinases such as Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, as well as the tyrosine kinase c-Met. Neratinib selectively inhibits the proliferation of 3T3 cells transfected with the HER2 (3T3/neu), as well as two other HER-2-overexpressing SK-Br-3 and BT474 cells with IC50 values of 2-3 nM, displaying >230-fold potency compared with non-transfected 3T3 cells as well as MDA-MB-435 and SW620 which are EGFR- and HER2-negative. Neratinib also inhibits the proliferation of EGFR-dependent A431 cells with an IC50 of 81 nM. Neratinib reduces HER2 receptor autophosphorylation in BT474 cells with an IC50 of 5 nM, and EGF-dependent phosphorylation of EGFR in A431 cells with IC50 of 3 nM. Blocking of HER-2 by Neratinib results in inhibition of downstream MAPK and Akt pathways with IC50 of 2 nM, more potently than Trastuzumab. Neratinib inhibits the cyclin D1 expression and the phosphorylation of the Rb-susceptibility gene production in BT474 cells with IC50 of 9 nM, leading to G1-S arrest and ultimately decreased cell proliferation.


    Kinase Assay: Neratinib is prepared as 10 mg/mL stocks in DMSO and diluted in 25 mM HEPES (pH 7.5; 0.002 ng/mL-20 μg/mL). Purified recombinant COOH-terminal fragments of HER2 (amino acids 676-1255) or epidermal growth factor receptor (EGFR) (amino acids 645-1186) [diluted in 100 mM HEPES (pH 7.5) and 50% glycerol] is 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 in 96-well ELISA plates. The kinase reaction is initiated by the addition of 40 μM ATP and 20 mM MgCl2and allowed to proceed for 1 hour at room temperature. Plates are washed, and phosphorylation is detected using Europium-labeled anti-phospho-tyrosine antibodies (15 ng/well). After washing and enhancement steps, signal is detected using a Victor2 fluorescence reader (excitation wavelength 340 nm, emission wavelength 615 nm). The concentration of Neratinib that inhibits receptor phosphorylation by 50% (IC50) is calculated from inhibition curves.


    Cell Assay: Cells (3T3, 3T3/neu, A431, BT474, SK-Br-3, MDA-MB-435, and SW480) are exposed to various concentrations of Neratinib for 2, or 6 days. Cell proliferation is determined using sulforhodamine B, a protein binding dye. Briefly, cells are fixed with 10% trichloroacetic acid and washed extensively with water. Cells are then stained with 0.1% sulforhodamine B and washed in 5% acetic acid. Protein-associated dye is solubilized in 10 mM Tris, and absorbance is measured at 450 nM. The concentration of Neratinib that inhibits cell proliferation by 50% (IC50) is determined from inhibition curves.

    In VivoOral administration of Neratinib significantly inhibits the growth of 3T3/neu xenografts, with inhibition of 34%, 53%, 98%, and 98% at dose of 10, 20, 40, and 80 mg/kg/day, respectively. Consistent with the inhibition of HER-2 phosphorylation by 84% within 1 hour of administration at 40 mg/kg/day, Neratinib inhibits the growth of BT474 xenografts by 70-82%, 67%, and 93% at dose of 5, 10, and 40 mg/kg/day, respectively. Neratinib is also effective against SK-OV-3 xenografts with inhibition of 31% and 85% at 5 and 60 mg/kg/day, respectively. Neratinib is less potent against EGFR-dependent A431 xenografts than HER-2-dependent tumors, with 32% and 44% inhibition at 5 and 20 mg/kg/day, respectively. Neratinib displays little activity against MCF-7 and MX-1 xenografts expressing low levels of HER-2 and EGFR, with only 28% inhibition at 80 mg/kg/day, suggesting that Neratinib has selective activity for cells expressing HER-2 or EGFR.
    Animal modelAthymic nude mice implanted s.c. with 3T3/neu, BT474, MCF-7, or SK-OV-3 cells
    Formulation & DosageFormulated in 0.5% methocellulose-0.4% polysorbate-80 (Tween 80); 80 mg/kg; Oral gavage
    References

    Cancer Res. 2004 Jun 1;64(11):3958-65.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    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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