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Neratinib

Cat. No. M1913
Neratinib Structure
Synonym:

HKI-272

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Free Sample (0.5-1 mg)  USD 0 In stock
5mg USD 30  USD30 In stock
10mg USD 50  USD50 In stock
25mg USD 80  USD80 In stock
50mg USD 110  USD110 In stock
100mg USD 170  USD170 In stock
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Quality Control
Biological Activity

Neratinib is a potent irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2 with IC50 of 92 nM and 59 nM, respectively. Neratinib inhibits the proliferation of EGFR-dependent A431 cells with an IC50 of 81 nM. Neratinib (HKI-272) also weakly inhibits tyrosine kinases KDR and Src with IC50 of 0.8 μM and 1.4 μM, respectively. Likewise, Neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC50 = 0.24 μM). Neratinib enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that Neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Moreover, Neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib (HKI-272) stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations.

Product Citations
Customer Product Validations & Biological Datas
Source ACS Chem Biol (2016). Figure 5. Neratinib (Abmole Bioscience)
Method FECH inhibition assay
Cell Lines K562 Cells
Concentrations 1 μM
Incubation Time 6 days
Results In line with the Kd values obtained from kinobead experiments, Vemurafenib, CUDC 101, Cyc-116, Linsitinib, MK-2461, Neratinib, GSK-690693, and Crenolanib decreased FECH binding to the PPIX beads by 50% or more compared to the DMSO control.
Source ACS Chem Biol (2016). Figure 4. Neratinib (Abmole Bioscience)
Method FECH inhibition assay
Cell Lines K562 Cells
Concentrations 1 μM
Incubation Time 6 days
Results We then subjected MK-2461, Neratinib, and Linsitinib to the same assay (1 μM for 6 days), and each drug clearly led to reduced heme levels indicating inhibition of FECH activity in K562 cells with Neratinib showing the most potent effect (60% reduction).
Source ACS Chem Biol (2016). Figure 3. Neratinib (Abmole Bioscience)
Method FECH binding
Cell Lines K562 Cells
Concentrations
Incubation Time
Results The basis of this assay is that proteins bound to a drug molecule are stabilized against heat induced unfolding and aggregation, and the extent of this protection is dose dependent.
Source ACS Chem Biol (2016). Figure 2. Neratinib (Abmole Bioscience)
Method FECH binding
Cell Lines
Concentrations
Incubation Time
Results Figure 2b−f show the full dose response data for five selected inhibitors, and the complete set of these plots can be found in Supporting Information Figure S1 and Table S1.
Protocol
Cell Experiment
Cell lines 3T3, 3T3/neu, A431, SK-Br-3, BT474, MDA-MB-435, and SW62 cells
Preparation method Cell Proliferation Assays.
Cells were plated in 96-well tissue culture plates (3T3, 3T3/neu, 5000 cells/well; A431, SK-Br-3, BT474, MDA-MB-435, and SW620, 10,000 cells/well). The following day, dilutions of compound (0.5 ng/ml–5 μg/ml) were added, and cells were cultured for 2 days (6 days for BT474). Cell proliferation was determined using sulforhodamine B, a protein binding dye. Briefly, cells were fixed with 10% trichloroacetic acid and washed extensively with water. Cells were then stained with 0.1% sulforhodamine B (Sigma-Aldrich) and washed in 5% acetic acid. Protein-associated dye was solubilized in 10 mm Tris, and absorbance was measured at 450 nm (Victor2). Inhibition of cell proliferation was calculated using the formula: percentage of inhibition = 100 − 100 (Td − To/Tc − To), where Td is the absorbance of drug treated cells, Tc is the absorbance of untreated cells, and To is the absorbance at the time of drug addition. To values were determined by plating cells separately and fixing them at the time of drug addition. The concentration of compound which inhibits cell proliferation by 50% (IC50) was determined from inhibition curves.
Concentrations 0.5 ng/ml-5 μg/ml
Incubation time 2 days
Animal Experiment
Animal models BT474, MCF-7, and SK-OV-3 tumour xenografts model in female athymic (nude) mice
Formulation 0.5% methocellulose-0.4% polysorbate-80 (Tween 80)
Dosages 40 or 60mg/kg daily for 20 days
Administration oral gavage
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information
Molecular Weight 557.04
Formula C30H29ClN6O3
CAS Number 698387-09-6
Purity 99.88%
Solubility DMSO 8 mg/mL
Storage at -20°C
References

[1] Zhao XQ, et al. Mol Pharmacol. Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo.

[2] Rabindran SK, et al. Cancer Res. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase.

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Keywords: Neratinib, HKI-272 supplier, EGFR/HER2, inhibitors

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