Research Area
Product Type
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CI-1033 (Canertinib) Chemical Structure
BIBW2992 (Afatinib)
BIBW2992 (Afatinib, Tomtovok, Tovok) irreversibly inhibits EGFR/HER2 including EGFRwt, EGFR L858R , EGFR L858R/T790M and HER2 with IC50 of 0.5 nM, 0.4 nM, 10 nM, 14 nM, respectively.
Erlotinib HCl
Erlotinib HCl also known as Tarceva, CP-358774, OSI-774, NSC-718781 is a HCL salt with IC50 of 2 nM for HER1/EGFR TK.
Gefitinib (Iressa)
Gefitinib (Iressa) also known as ZD-1839 & Iressa is a novel potent EGFR tyrosine kinase & Akt phosphorylations inhibitor with IC50 of 37, 26 and 57 nM.
Lapatinib Ditosylate (Tykerb)
Lapatinib (Tyverb, GW-572016, GW-2016) is a potent purified EGFR and ErbB-2 inhibitor with IC50 of 10.2 and 9.8 nM, respectively.
Vandetanib (Zactima)
Vandetanib (Zactima) is a VEGFR and EGFR antagonist and a tyrosine kinase inhibitor with IC50 of 60, 90, 40 nM for HUVEC proliferation, PC-9 cells and tyrosine kinase activity, respectively.
BMS-599626 (AC480)
BMS-599626 (AC480) is a highly selective pan-HERKinase inhibitor with IC50 of 20 and 30 nM for the inhibition of HER1and HER2, respectively.
PD153035 HCl
PD153035 HCl is an inhibitor of EGFR, competitive with ATP. EGF Receptor: IC50 = 25 pM (Ki = 6 pM)
XL647
Inhibitor of the EGFR and ErbB2 with IC50 0.3 and 16 nM respectively.
AG-490
AG 490 is a potent epidermal growth factor receptor kinase autophosphorylation inhibitor with an IC50 of 100 nM and 56.8 μM for EGFR and JAK, respectively.
CP-724714
CP-724714 is a HER-2 tyrosine kinase inhibitor, IC50 of 15 ng/ml
Biological Activity
| Information | CI-1033 is a potent tyrosine kinase 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. | |||||
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 ℃. The reaction is started by adding [32P]ATP, and the plate is incubated at 25 ℃ 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 ℃ 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 |
| Method: | 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 |
| Dosages: | ~18 mg/kg |
| Administration: | Administered by oral |
Product Information
| Molecular Weight (WM): | 485.94 |
|---|---|
| Formula: | C24H25ClFN5O3 |
| CAS No.: | 267243-28-7 |
| Synonyms: |
PD-183805
|
| Dissolve in (25°C): | DMSO ≥6mg/mL |
| Water <1mg/mL | |
| Ethanol <1mg/mL | |
| Storage: | 2 years-20°CPowder |
| 1 week-4°Cin DMSO | |
| 1 month-80°in DMSO |
Quality Control & MSDS
Research Area
Notes:
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(B–C) LNCaP (B) and LNCaP-AI (C) cells were transiently transfected with sPLA2-IIa(-800)-Luc (0.5 lg). The cells were then treated with Erlotinib (20 lM), Gefitinib (20 lM), Lapatinib (20 lM), CI-1033 (8 lM), LY294002 (20 lM) and Bortezomib (20 lM) without or with EGF (100 ng/ml) for 24 h. Luciferase assay was performed according to a standard protocol with Renilla luciferase as an internal control. Data are presented as the mean (±SD) of duplicate values of a representative experiment that was independently repeated for five times.
(B–C) LNCaP (B) and LNCaP-AI (C) cells were transiently transfected with sPLA2-IIa(-800)-Luc (0.5 lg). The cells were then treated with Erlotinib (20 lM), Gefitinib (20 lM), Lapatinib (20 lM), CI-1033 (8 lM), LY294002 (20 lM) and Bortezomib (20 lM) without or with EGF (100 ng/ml) for 24 h. Luciferase assay was performed according to a standard protocol with Renilla luciferase as an internal control. Data are presented as the mean (±SD) of duplicate values of a representative experiment that was independently repeated for five times.
Data from [Carcinogenes 2010.September;31:1948–1955 ] CI-1033 (Canertinib) purchased from Selleck
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After starved in serum-free medium for 24h, Breast cancer cells incubated with the indicated concentrations of CI-1033 for 3h,followed by 15-minute stimolation of 100ng/ml EGF
After starved in serum-free medium for 24h, Breast cancer cells incubated with the indicated concentrations of CI-1033 for 3h,followed by 15-minute stimolation of 100ng/ml EGF
Data independently produced by Dr Zhang of Tianjin Medical University CI-1033 (Canertinib) purchased from Selleck
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H1975 cells were pretreated with 10nm EGF for 15 min and then treated with the indicated concentrations of CI-1033 for 2 hours.
H1975 cells were pretreated with 10nm EGF for 15 min and then treated with the indicated concentrations of CI-1033 for 2 hours.
Data independently produced by Dr Kian Kani of Cedars-Sinai Medical Center CI-1033 (Canertinib) purchased from Selleck
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LNCaP-AI cells were starved in 1% stripped medium for 24 h. The cells were then treated with Erlotinib (20 lM), Gefitinib (20 lM), Lapatinib (20 lM), CI-1033 (8 lM), LY294002 (20 lM) and Bortezomib (20 lM) for 24 h. Cell culture medium was collected from each sample and subjected to ELISA for sPLA2-IIa. The condition medium samples were diluted 10 times for ELISA. Average of duplicate samples was converted to nanogram per milliliter against standard curve. The data represent one of five repeated experiments.
LNCaP-AI cells were starved in 1% stripped medium for 24 h. The cells were then treated with Erlotinib (20 lM), Gefitinib (20 lM), Lapatinib (20 lM), CI-1033 (8 lM), LY294002 (20 lM) and Bortezomib (20 lM) for 24 h. Cell culture medium was collected from each sample and subjected to ELISA for sPLA2-IIa. The condition medium samples were diluted 10 times for ELISA. Average of duplicate samples was converted to nanogram per milliliter against standard curve. The data represent one of five repeated experiments.
Data from [Carcinogenesis 2010.September;31:1948–1955] CI-1033 (Canertinib) purchased from Selleck
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(B–C) LNCaP (B) and LNCaP-AI (C) cells were transiently transfected with sPLA2-IIa(-800)-Luc (0.5 lg). The cells were then treated with Erlotinib (20 lM), Gefitinib (20 lM), Lapatinib (20 lM), CI-1033 (8 lM), LY294002 (20 lM) and Bortezomib (20 lM) without or with EGF (100 ng/ml) for 24 h. Luciferase assay was performed according to a standard protocol with Renilla luciferase as an internal control. Data are presented as the mean (±SD) of duplicate values of a representative experiment that was independently repeated for five times. |
Data from [Carcinogenes 2010.September;31:1948–1955 ]
After starved in serum-free medium for 24h, Breast cancer cells incubated with the indicated concentrations of CI-1033 for 3h,followed by 15-minute stimolation of 100ng/ml EGF
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Data independently produced by Dr Zhang of Tianjin Medical University
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