Canertinib (CI-1033)

Canertinib (CI-1033) is a pan-ErbB inhibitor for EGFR and ErbB2 with IC50 of 1.5 nM and 9.0 nM, no activity to PDGFR, FGFR, InsR, PKC, or CDK1/2/4. Phase 3.

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Canertinib (CI-1033) Chemical Structure

Canertinib (CI-1033) Chemical Structure
Molecular Weight: 485.94

Validation & Quality Control

Customer Reviews(7)

Quality Control & MSDS

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Product Description

Biological Activity

Description Canertinib (CI-1033) is a pan-ErbB inhibitor for EGFR and ErbB2 with IC50 of 1.5 nM and 9.0 nM, no activity to PDGFR, FGFR, InsR, PKC, or CDK1/2/4. Phase 3.
Targets EGFR [1] ErbB2 [1]
IC50 1.5 nM 9.0 nM
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]
Features First kinase inhibitor to show irreversible activity and to have entered clinical trials (serving as a template for further development).

Protocol(Only for Reference)

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
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 orally
Solubility 30% propylene glycol, 5% Tween 80, 65% D5W, , 10 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

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.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-13)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00362986 Completed Dermatologic Complications|Unspecified Adult Solid Tumor, Protocol Specific National Cancer Institute (NCI)|North Central Cancer Treatment Group October 2006 Phase 3
NCT00050830 Completed Lung Neoplasms Pfizer January 2003 Phase 2
NCT00051051 Completed Breast Neoplasms Pfizer December 2002 Phase 2
NCT00174356 Completed Carcinoma, Non-Small Cell Lung Pfizer December 2002 Phase 1

Chemical Information

Download Canertinib (CI-1033) SDF
Molecular Weight (MW) 485.94
Formula

C24H25ClFN5O3

CAS No. 267243-28-7
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms PD183805
Solubility (25°C) * In vitro DMSO 2 mg/mL (4 mM)
Water <1 mg/mL (<1 mM)
Ethanol 9 mg/mL (18 mM)
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W, 10 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name N-(4-(3-chloro-4-fluorophenylamino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide

Research Area

Customer Reviews (7)


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Rating
Source Carcinogenesis 2010 31, 1948–1955. Canertinib (CI-1033) purchased from Selleck
Method Luciferase assay
Cell Lines LNCaP-AI cells, LNCaP cells
Concentrations 20 μM
Incubation Time 24h
Results EGF significantly stimulates the promoter activity of sPLA2-IIa gene in both LNCaP and LNCaP-AI cells (shown in LNCaP-AI cells), whereas CI-1033 and other inhibitors tested downregulated the promoter activity both at the basal level (shown in LNCaP cells) and in response to EGF stimulation (shown in LNCaP-AI cells).

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Rating
Source Carcinogenesis 2010 31, 1948–1955. Canertinib (CI-1033) purchased from Selleck
Method ELISA
Cell Lines LNCaP-AI cells
Concentrations 20 μM
Incubation Time 24 h
Results Lapatinib, LY294002 and Bortezomib significantly inhibited sPLA2-IIa secretion, whereas Erlotinib, Gefitinib and CI-1033 had a moderate effect in LNCaP-AI cells.

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Rating
Source Cell Cycle 2009 13, 2050-2056. Canertinib (CI-1033) purchased from Selleck
Method Western Blot
Cell Lines H1993 cells
Concentrations 1.5 uM
Incubation Time 4 h
Results We pretreated the cells with SU11274 for 48 h before adding, for the final 4 h, the PKC δ inhibitor rottlerin, GO6976 (an inhibitor blocking the activities of classical PKCs only), or CI-1033 (an irreversible ErbB TKI). Inclusion of rottlerin for the final 4 h effectively inhibited the re-activation of Akt, ErbB2 and ErbB3 (Fig. 4B). GO6976 was ineffective, while CI-1033 had an intermediate impact on the restoration of ErbB/AKT signaling.

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Rating
Source Cell Cycle 2009 13, 2050-2056. Canertinib (CI-1033) purchased from Selleck
Method Cell proliferation assay
Cell Lines H1993 cells
Concentrations 1.5uM
Incubation Time 6 d
Results After up to 6 days of incubation, SU11274 alone only moderately inhibited H1993 cell growth, while the combination of SU121274 and CI-1033 was much more effective. Surprisingly, treatment with CI-1033 alone had no impact on cell growth.

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Rating
Source Dr. Zhang of Tianjin Medical University. Canertinib (CI-1033) purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-0.05 nM
Incubation Time 3 h
Results CI-1033 treatment resulted in a reduction of EGFR phosphorylation in Breast cancer cells.

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Rating
Source Dr. Kian Kani of Cedars-Sinai Medical Center. Canertinib (CI-1033) purchased from Selleck
Method Western blot
Cell Lines H1975 cells
Concentrations 10-300 nM
Incubation Time 2 h
Results CI-1033 treatment resulted in a reduction of EGFR phosphorylation in H1975 cells.

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Rating
Source Canertinib (CI-1033) purchased from Selleck
Method Western Blotting
Cell Lines A431 cells
Concentrations 10nM
Incubation Time 30mins
Results Conclusion-P-EGFR (Tyr845) signal is inhibited in varying degree with EGF stimulation, and is not detectable without EGF stimulation. Inhibition results in table below right

Product Citations (5)

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