Canertinib (CI-1033) is a pan-erbB tyrosine kinase inhibitor. Canertinib is a clinically promising agent that is active against all four members of the erbB receptor tyrosine kinase family. Canertinib suppresses heregulin-stimulated tyrosine phosphorylation of erbB2, erbB3 and erbB4 with IC50 of 5, 14 and 10 nM, respectively. In vitro studies of human cancer cell lines indicate that Canertinib (CI-1033) results in prompt, potent, and sustained inhibition of tyrosine kinase activity. This inhibition is highly selective for erbB1 (epidermal growth factor receptor), erbB2, erbB3, and erbB4 without inhibiting tyrosine kinase activity of receptors such as platelet-derived growth factor receptor, fibroblast growth factor receptor, and insulin receptor, even at high concentrations. Canertinib (CI-1033) shows high levels of inhibition in A431 cells expressing EGFR with IC50 of 7.4 nM. In addition, Canertinib inhibits the proliferation of TT, TE2, TE6 and TE10 cells significantly at 0.1 nM.
| Cell Experiment | |
|---|---|
| Cell lines | SK-N-AS, LA1-55N, SK-N-SH, SH-EP, CHP-134 and SH-SY5Y cell lines |
| Preparation method | Growth Analysis. Cells were plated at 100,000 cells per well in a 6 well plate. After cells became adherent, drug was added and refreshed every 24 hours. After 3 or 7 days of triplicate treatments with 0, 0.01, 0.1, 1, 3, or 5 μM CI-1033 or 0, 0.1, 1, 3, 5, or 10 μM erlotinib, media and dead cells were removed by washing with PBS. Intact nuclei were extracted by addition of a 0.01M hepes-0.015 M MgCl2 buffer for 5 minutes, followed by addition of 5% Bretol (ethyl hexadecyldimethylammonium bromide) in water and agitation for 10 minutes. Nuclei were then fixed with a 0.9% NaCl and 0.5% Formalin solution in water and counted using the ViCell Cell Viability Analyzer (Beckman Coulter, Fullerton, CA) as previously described 22. IC50 values were calculated using Microsoft Excel with a best fit trendline. |
| Concentrations | 0, 0.01, 0.1, 1, 3, or 5 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | 12 week old NOD-SCID-IL2R gamma knockout mice bearing Subcutaneous SK-N-SH xenografts |
| Formulation | water |
| Dosages | 30 mg/kg daily for 18 days |
| Administration | gavage |
| Molecular Weight | 485.94 |
| Formula | C24H25ClFN5O3 |
| CAS Number | 267243-28-7 |
| Solubility (25°C) | Ethanol ≥ 7 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.
[4] Slichenmyer WJ, et al. Semin Oncol. CI-1033, a pan-erbB tyrosine kinase inhibitor.
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