Home Protein Tyrosine Kinase EGFR inhibitor - HER2 inhibitor Canertinib (CI-1033)

Canertinib (CI-1033)

Catalog No.S1019 Synonyms: PD183805

For research use only.

Canertinib (CI-1033, PD183805) 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.

Canertinib (CI-1033) Chemical Structure

CAS No. 267243-28-7

Selleck's Canertinib (CI-1033) has been cited by 42 publications

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Biological Activity

Description Canertinib (CI-1033, PD183805) 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.
Features First kinase inhibitor to show irreversible activity and to have entered clinical trials (serving as a template for further development).
Targets
EGFR [1]
(Cell-free assay)		 ErbB2 [1]
(Cell-free assay)
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]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human HCC827 cells M3zLSnBzd2yrZnXyZZRqd25iYYPzZZk> MXi3NkBp NVXS[WZiSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDIR2M5OjdiY3XscJMhcGG{Yn;ybY5oKEWJRmKg[IVtKEV5NE[tRVc2OCCvdYThcpQh[W[2ZYKgO|IhcHK|IHL5JG1VWyCjc4PhfUwhUUN3ME2wMlAxOSEQvF2= NFLzXGgzOjN|OUO0Ni=>
A431 cells M2qyfGZ2dmO2aX;uJIF{e2G7 NIPpTW5KdmirYnn0bY9vKG:oIFXHSk1{fGmvdXzheIVlKGG3dH;wbI9{eGixconsZZRqd25ib3[gSWdHWiCnbor5cYUhcW5iQUSzNUBk\WyuczDk[ZRm[3SnZDDifUBqdW23bn;icI91fGmwZzygTWM2OD1yLkCwO|Qh|ryP M3\kOVExPzV|NEe1
MDA-MB 453 cells Mn;RSpVv[3Srb36gZZN{[Xl? NFz0Z3VKdmirYnn0bY9vKG:oIHH1eI9xcG:|cHjvdplt[XSrb36gc4YhTVKEQkKgdoVk\XC2b4Kgb4lv[XOnIHnuJG1FSS2PQjC0OVMh[2WubIOsJGlEPTB;MD6wNFkh|ryP NYnJdmxUOTB5NUO0O|U>
human BT474 cells M3zuT3Bzd2yrZnXyZZRqd25iYYPzZZk> MVezJIRigXN? MmX4RY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCEVES3OEBk\WyuczDveoVz\XiycnXzd4lv\yCHUlLiNkBi\nSncjCzJIRigXNiYomgcYV1cHmuZX7lJIJtfWVic4ThbY5qdmduIFXDOVA:OC5yMTFOwG0> NGjOSVkyQTB{OESyOC=>
mouse BAF3 cells M2n1SWZ2dmO2aX;uJIF{e2G7 MYDJcohq[mm2aX;uJI9nKEKuazDlfJBz\XO|ZXSgbY4hdW:3c3WgRmFHOyClZXzsd{Bie3Onc4Pl[EBieyCleYTveI95cWOrdImsJGlEPTB;MD6wNlkh|ryP MnHDNVg3Pjd|MUK=
human HN5 cells NFznZoVRem:uaX\ldoF1cW:wIHHzd4F6 MXqzJIRigXN? NXWzT3FiSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDIUlUh[2WubIOgc5ZmemW6cILld5NqdmdiRVfGVkBi\nSncjCzJIRigXNiYomgcYV1cHmuZX7lJIJtfWVic4ThbY5qdmduIFXDOVA:OC5yNTFOwG0> Mn:3NVkxOjh2MkS=
human NCI-H1975 cells MkfRVJJwdGmoZYLheIlwdiCjc4PhfS=> MYq3NkBp MoLoRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCQQ1mtTFE6PzViY3XscJMhcGG{Yn;ybY5oKEWJRmKgUFg2QFJxVEe5NG0hdXW2YX70JIFnfGW{IEeyJIhzeyCkeTDNWHMh[XO|YYmsJGlEPTB;MD6wOlQh|ryP MkLpNlI{Ozl|NEK=
human A431 cells MWPQdo9tcW[ncnH0bY9vKGG|c3H5 MYO3NkBp NV\qT5pSSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDBOFMyKGOnbHzzJI93\XKneIDy[ZN{cW6pIFXHSnIh[W[2ZYKgO|IhcHK|IHL5JG1VWyCjc4PhfUwhUUN3ME2wMlE2KM7:TR?= NFXIfZAzOjN|OUO0Ni=>
human A549 cells NVTkSJl4WHKxbHnm[ZJifGmxbjDhd5NigQ>? MlXRO|IhcA>? NHrURmlCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIFG1OFkh[2WubIOg[ZhxemW|c3nu[{B4cWymIIT5dIUhTUeIUjDjc4V5eHKnc4Ppcochcy2UYYOgcZV1[W62IHHmeIVzKDd{IHjyd{BjgSCPVGOgZZN{[XluIFnDOVA:OS53OTFOwG0> NGjBWIUzOjN|OUO0Ni=>
mouse BAF3 cells NHzkN4hHfW6ldHnvckBie3OjeR?= NInMfWVKdmirYnn0bY9vKG:oIFrBT|Mh\XiycnXzd4VlKGmwIH3veZNmKEKDRkOgZ4VtdHNiYYPz[ZN{\WRiYYOgZ5l1d3SxeHnjbZR697zOIFnDOVA:OiEQvF2= NGPYUGwyQDZ4N{OxNi=>
human HL7702 cells NHPBeXdRem:uaX\ldoF1cW:wIHHzd4F6 M4L6V|czKGh? MUDBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEiON{ewNkBk\WyuczDlfJBz\XO|aX7nJJdqdHRidInw[UBGT0[UIHHmeIVzKDd{IHjyd{BjgSCPVGOgZZN{[XluIFnDOVA:Oi5|IN88US=> NW\FbYxoOjJ|M{mzOFI>
human A431 cells NUHJSoxCTnWwY4Tpc44h[XO|YYm= MnHWNUDPxE1? NU[4PVB3OSCq NF\hVmJKenKndnXyd4ljdGViaX7obYJqfGmxbjDv[kBGT0[UIHH1eI9xcG:|cHjvdplt[XSrb36gbY4hcHWvYX6gRVQ{OSClZXzsd{BifCBzIIXNJIlv[3WkYYTl[EBnd3JiMTDodkBnd2yub4fl[EBjgSClb33wc5Vv\CC5YYPoJI92fCCvZXHzeZJm\CB3IHjyd{Bxd3O2IFXHSkBi\GSrdHnvckBjgSCZZYP0[ZJvKGKub4T0bY5oKGGwYXz5d4l{ M3jEV|I1QTByNUm0
human LNCaP cells NEfTZ3BHfW6ldHnvckBie3OjeR?= MmezNVAh|ryP MUKyJIg> MofxTY5pcWKrdHnvckBw\iCjdYTvdIhwe3Cqb4L5cIF1cW:wIH;mJIludXWwb4Dy[YNqeGm2YYTl[EBndGGpLYTh[4dm\CCEbYig[ZhxemW|c3XkJIlvKGi3bXHuJGxPS2GSIHPlcIx{KGG|c3Xzd4VlKGG|IHnuZ49zeG:{YYTpc44hd2ZiW{OyVH1CXFBiYYSgNVAhfU1icILleJJm[XSnZDDmc5IhOiCqcoOgZoVnd3KnIITyZY5{\mWldHnvckBjgSCrbX31co9jdG:2IHHuZYx6e2m| NFP2cXAyQDZ4N{OxNi=>
NCI-H1975 cells M4\CcWdzd3e2aDDpcohq[mm2aX;uJIF{e2G7 MYW0PEBp MnPPTY5pcWKrdHnvckBw\iCHR1\SJGw5PTiUL2S3PVBOKG23dHHueEBqdiCqdX3hckBPS0lvSEG5O|Uh[2WubIOgZZN{\XO|ZXSgZZMh\3Kxd4ToJIlvcGmkaYTpc44h[W[2ZYKgOFghcHK|IHL5JG1VXCCjc4PhfS=> M3XybFI1QTByNUm0
Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Growth inhibition assay Cell viability 28638122
Western blot p-FAK / FAK / p-AKT / AKT ; pEGFR / EGFR / p-HER2 / HER2 / p-HER3 / HER3 / MUC4 25686822
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]

Protocol (from 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 Research:[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.
  • (Only for Reference)
Animal Research:[1]
  • Animal Models: A431 xenografts established in nude mice
  • Dosages: ~18 mg/kg
  • Administration: Administered orally
  • (Only for Reference)

Solubility (25°C)

In vitro

 Ethanol 9 mg/mL
(18.52 mM)
DMSO 2 mg/mL
(4.11 mM)
Water Insoluble

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
30% propylene glycol, 5% Tween 80, 65% D5W
For best results, use promptly after mixing.

 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.

Chemical Information

Molecular Weight 485.94
Formula

C24H25ClFN5O3
CAS No. 267243-28-7
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles C=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

mg/kg g μL

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00050830 Completed Drug: CI 1033 Lung Neoplasms Pfizer January 2003 Phase 2
NCT00174356 Completed Drug: CI 1033|Drug: PACLITAXEL|Drug: CARBOPLATIN Carcinoma Non-Small Cell Lung Pfizer December 2002 Phase 1
NCT00051051 Completed Drug: CI-1033 Breast Neoplasms Pfizer December 2002 Phase 2

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

Question 1:
I would like to know which is the best option/solvent to dilute CI-1033 (Catalog No.S1019) for in vivo experiments. (I am treating mice at 30mg/mL of CI-1033.)

Answer:
The compound in the formulation recommended (30% Propylene glycol, 5% Tween 80, 65% D5W) on our product page at 30mg/ml is suspension. It’s fine for oral gavage.

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