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.
Cell Death Dis. 2021 Feb 15;12(2):179.
Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors
Neratinib purchased from AbMole
Int J Clin Exp Med. 2019 Aug 30;12(8):10373-10379.
Neratinib inhibits the malignant phenotype via inhibiting the HER2 in osteosarcoma cells
Neratinib purchased from AbMole
ACS Chem Biol. 2016 May 20;11(5):1245-54.
Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors
Neratinib purchased from AbMole
Cell Experiment | |
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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 | |
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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 |
Molecular Weight | 557.04 |
Formula | C30H29ClN6O3 |
CAS Number | 698387-09-6 |
Solubility (25°C) | DMSO 8 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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.
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