Neratinib (HKI-272)

Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM; weakly inhibits KDR and Src, no significant inhibition to Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. Phase 3.

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Neratinib (HKI-272) Chemical Structure

Neratinib (HKI-272) Chemical Structure
Molecular Weight: 557.04

Validation & Quality Control

Customer Reviews(3)

Quality Control & MSDS

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Product Description

Biological Activity

Description Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM; weakly inhibits KDR and Src, no significant inhibition to Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. Phase 3.
Targets HER2 [1] EGFR [1] KDR [1] Src [1] PDK-1 [1]

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IC50 59 nM 92 nM 800 nM 1.4 μM >5 μM
In vitro 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. [1]
In vivo Oral 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. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Cell-free autophosphorylation assay using time-resolved fluorometry 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 MgCl2 and 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: [1]

Cell lines 3T3, 3T3/neu, A431, BT474, SK-Br-3, MDA-MB-435, and SW480
Concentrations Dissolved in DMSO, final concentrations 0.5 ng/mL-5 μg/mL
Incubation Time 2 or 6 days
Method Cells 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.

Animal Study: [1]

Animal Models Female athymic (nude) mice implanted s.c. with 3T3/neu, BT474, MCF-7, or SK-OV-3 cells
Formulation Formulated in 0.5% methocellulose-0.4% polysorbate-80 (Tween 80)
Dosages ~80 mg/kg/day
Administration Gavage
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 5 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
1

References

[1] Rabindran SK, et al. Cancer Res, 2004, 64(11), 3958-3965.

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01128842 Completed Advanced Malignant Solid Tumors Puma Biotechnology, Inc. 2010-04 Phase 1
NCT01111825 Recruiting Breast Cancer Puma Biotechnology, Inc. 2010-04 Phase 1|Phase 2
NCT01142063 Completed Healthy Puma Biotechnology, Inc. 2010-06 Phase 1
NCT01494662 Recruiting Breast Cancer Dana-Farber Cancer Institute|Translational Breast Cancer Research Consortium 2012-02 Phase 2
NCT00932464 Withdrawn Healthy Puma Biotechnology, Inc. 2012-08 Phase 1

Chemical Information

Download Neratinib (HKI-272) SDF
Molecular Weight (MW) 557.04
Formula

C30H29ClN6O3

CAS No. 698387-09-6
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 2 mg/mL (3 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 5 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

Research Area

Customer Reviews (3)


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Rating
Source Cancer Discovery, 2012, 2, 458-471. Neratinib (HKI-272) purchased from Selleck
Method Western Blot
Cell Lines SKMG3
Concentrations 200-1800 nM
Incubation Time 3 day
Results Immunoblots of whole-cell lysates from SKMG3 cells treated with either inhibitor showed that CI-1033 inhibited EGFR phosphorylation less effectively than HKI-272 (Fig. C).

Click to enlarge
Rating
Source Cancer Discovery, 2012, 2, 458-471. Neratinib (HKI-272) purchased from Selleck
Method Cell Death Assay
Cell Lines Glioma & Lung cancer cell lines
Concentrations 125-2000 nM
Incubation Time 5 day
Results HKI-272 induced cell death in SF268 and SKMG3 cells but not in EGFR wild-type GBM (SF295, 8-MG-BA), lung cancer cells (H460), or human astrocytes (NHA; Fig. A).

Click to enlarge
Rating
Source Cancer Discov, 2013, 3(2), 224-37. Neratinib (HKI-272) purchased from Selleck
Method Colony assays
Cell Lines MCF10A cells
Concentrations 0.5 μmol/L
Incubation Time a week
Results Treatment with lapatinib and neratinib inhibited the growth of these invasive colonies.

Product Citations (5)

Tech Support & FAQs

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