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 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 models||12 week old NOD-SCID-IL2R gamma knockout mice bearing Subcutaneous SK-N-SH xenografts|
|Dosages||30 mg/kg daily for 18 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||Ethanol ≥ 7 mg/mL|
Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo.
Richards KN, et al. Cancer. 2010 Jul 1;116(13):3233-43. PMID: 20564646.
Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non small-cell lung cancer.
Jänne PA, et al. J Clin Oncol. 2007 Sep 1;25(25):3936-44. PMID: 17761977.
Administration of CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: a phase I pharmacokinetic and food effect study.
Calvo E, et al. Clin Cancer Res. 2004 Nov 1;10(21):7112-20. PMID: 15534081.
CI-1033, a pan-erbB tyrosine kinase inhibitor.
Slichenmyer WJ, et al. Semin Oncol. 2001 Oct;28(5 Suppl 16):80-5. PMID: 11706399.
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