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CI-1033(Canertinib)

产品号 S1019 公司名称 Selleck Chemicals
CAS号 267243-28-7 公司网站 http://www.selleckchem.com
分子式 C24H25ClFN5O3 电 话 (877) 796-6397
分子量 485.9384032 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72462

产品价格信息

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产品别名

标题
CI-1033(Canertinib)
IUPAC标准名
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide
IUPAC传统名
canertinibumcanertinib
别名
PD-183805
Canertinib
PD183805

产品登记号

CAS号 267243-28-7

产品性质

作用靶点 EGFR
作用靶点 HER2
成盐信息 Free Base
溶解度 DMSO
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description CI-1033 is a potent inhibitor of EGFR and ErbB2 with IC50 of 1.5 nM and 9.0 nM, respectively.
Targets EGFR ErbB2
IC50 1.5 nM 9.0 nM [1]
In Vitro CI-1033 shows excellent potency for irreversible inhibition of erbB2 autophosphorylation in MDA-MB 453 cells. CI-1033 also shows high permeability in Caco-2 cells and inhibits secretory transport of vinblastine, which indicates that CI-1033 is a likely inhibitor of the P-gp. [1] CI-1033 alone, significantly suppresses constitutively activated Akt and MAP kinase. In combination with gemcitabine, CI-1033 inhibits Akt and prevents increased levels of MAPK phosphorylation. CI-1033 stimulates p27 expression and p38 phosphorylation in MDA-MB-453 cells. [2] CI-1033 is highly specific to the erbB receptor family and not sensitive to PGFR, FGFR or IR even at 50 μM. CI-1033 shows high levels of inhibition in A431 cells expressing EGFR with IC50 of 7.4 nM. CI-1033 suppresses heregulin-stimulated tyrosine phosphorylation of erbB2, erbB3 and erbB4 with IC50 of 5, 14 and 10 nM, respectively. CI-1033 also inhibits expression of pp62c-fos in response to heregulin. [3] CI-1033 is predicted to modify Cys773 covalently within the ATP binding site of the HER2 kinase and enhances destruction of both mature and immature ErbB-2 molecules. [4] CI-1033 induces a significant decrease in measurable phosphorylation of tyrosine residues 845 and 1068 of EGFR, which are responsible for Src and Ras/MAPK signaling respectively. The corresponding residues of Her-2, tyrosine residues 877 and 1248 are dephosphorylated significantly by CI-1033 at a concentration of 3 μM or higher. CI could block EGFR internalization and increase the rate of apoptosis in primary osteosarcoma cells in a titratable fashion. [5] In addition, CI-1033 inhibits the proliferation of TT, TE2, TE6 and TE10 cells significantly at 0.1 nM. [6]
In Vivo CI-1033 shows impressive activity against A431 xenografts in nude mice at 5 mg/kg of body weight. [1] CI-1033 (20 to 80 mg/kg/d) achieves a high degree of tumor regressions in H125 xenograft models. [3] Oral administration of CI-1033 causes a marked inhibition of growth in TT, TE6 and TE10 xenografts in nude mice, without animal death and <10% weight="" loss.="">[6]
Clinical Trials Phase II trials have been completed in patients with metastatic breast cancer.
Features CI-1033 is the first kinase inhibitor showing irreversible activity to enter clinical trials and has become a template for further development.
Combination Therapy
Description CI-1033 (6 μM) combined with SN-38 (active metabolite of Irinotecan, 12 nM) show synergistic cytotoxicity in T98G cells. CI-1033 (8 μM) combined with SN-38 (10 nM) enhance the effect of SN-38 to delay T98G cells at G2-M phase. [7]
Protocol
Kinase Assay [1]
Tyrosine Kinase Assays Enzyme assays for determination of IC50 are performed in 96-well filter plates in a total volume of 0.1 mL, containing 20 mM Hepes, pH 7.4, 50 mM sodium vanadate, 40 mM magnesium chloride, 10 μM adenosine triphosphate (ATP) containing 0.5 mCi of [32P]ATP, 20 mg of polyglutamic acid/tyrosine, 10 ng of EGFR tyrosine kinase, and appropriate dilutions of CI-1033. All components except the ATP are added to the well and the plate is incubated with shaking for 10 min at 25 °C. The reaction is started by adding [32P]ATP, and the plate is incubated at 25 °C for another 10 min. The reaction is terminated by addition of 0.1 mL of 20% trichloroacetic acid (TCA). The plate is kept at 4 °C for at least 15 min to allow the substrate to precipitate. The wells are then washed five times with 0.2 mL of 10% TCA and 32P incorporation determined with a Wallac β plate counter.
Cell Assay [6]
Cell Lines TT, TE2, TE6 and TE10 cells
Concentrations 0.1-5.0 nM
Incubation Time 1, 3, 5 and 7 days
Methods Cells (1 × 104) are seeded in each well of a 24-well plastic culture plate and left overnight in DMEM or RPMI-1640 supplemented with 10% FBS. The next morning, the cells are treated with the indicated concentrations of CI-1033 (0.1-5.0 nM) for varying periods (1, 3, 5 and 7 days). After treatment, the cells are counted using a Coulter counter. The percent of cell proliferation is calculated by this formula: treatment cell number/control cell number × 100 for each time period.
Animal Study [1]
Animal Models A431 xenografts established in nude mice
Formulation In solution as the isethionate salts
Doses ~18 mg/kg
Administration Administered orally
References
[1] Smaill JB et al. J Med Chem. 2000; 43(7): 1380-1397.
[2] Nelson JM et al. J Biol Chem. 2001; 276(18): 14842-14827.
[3] Slichenmyer WJ et al. Semin Oncol. 2001; 28(5 Suppl 16): 80-85.
[4] Citri A et al. EMBO J. 2002; 21(10): 2407-2417.
[5] Hughes DP et al. Pediatr Blood Cancer. 2006; 46(5): 614-623.
[6] Ako E et al. Oncol Rep. 2007; 17(4): 887-893.
[7] Erlichman C, et al. Cancer Res, 2001, 61(2), 739-748.