Canertinib (CI-1033)

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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	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]
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
Dosages	~18 mg/kg
Administration	Administered orally
Solubility	30% propylene glycol, 5% Tween 80, 65% D5W, 10 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT00051051	Completed	Breast Neoplasms	Pfizer	2002-12	Phase 2
NCT00174356	Completed	Carcinoma, Non-Small Cell Lung	Pfizer	2002-12	Phase 1
NCT00050830	Completed	Lung Neoplasms	Pfizer	2003-01	Phase 2
NCT00362986	Completed	Dermatologic Complications|Unspecified Adult Solid Tumor, Protocol Specific	National Cancer Institute (NCI)|North Central Cancer Treatment Group	2006-10	Phase 3

Chemical Information

Download Canertinib (CI-1033) SDF

Chemical Name	N-(4-(3-chloro-4-fluorophenylamino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide

Customer Reviews (7)

Click to enlarge	Rating
	Source	Cell Cycle 8, 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.

Product Citations (4)

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  Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. [Vivanco I, et al. Cancer Discov 2012;2(5):458-71]

  
  PubMed: 22588883


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  The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin. [Choi W, et al. J Cell Sci 2010;123(Pt 18):3102-11]

  
  PubMed: 20736300


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  Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer. [Dong Z, et al. Carcinogenesis 2010;31(11):1948-55]

  
  PubMed: 20837598