Canertinib (CI-1033)

Catalog No.S1019 Synonyms: PD183805

Canertinib (CI-1033) Chemical Structure

Molecular Weight(MW): 485.94

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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Cited by 19 Publications

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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.
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 MYrQdo9tcW[ncnH0bY9vKGG|c3H5 NICz[HY4OiCq NGfSd5pCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIFjDR|gzPyClZXzsd{Bp[XKkb4LpcochTUeIUjDk[YwhTTd2Nj3BO|UxKG23dHHueEBi\nSncjC3NkBpenNiYomgUXRUKGG|c3H5MEBKSzVyPUCuNFAyKM7:TR?= MYeyNlM{QTN2Mh?=
A431 cells M37lN2Z2dmO2aX;uJIF{e2G7 NEXDZ|NKdmirYnn0bY9vKG:oIFXHSk1{fGmvdXzheIVlKGG3dH;wbI9{eGixconsZZRqd25ib3[gSWdHWiCnbor5cYUhcW5iQUSzNUBk\WyuczDk[ZRm[3SnZDDifUBqdW23bn;icI91fGmwZzygTWM2OD1yLkCwO|Qh|ryP NFTRcW4yODd3M{S3OS=>
MDA-MB 453 cells M17TeGZ2dmO2aX;uJIF{e2G7 NImxSHFKdmirYnn0bY9vKG:oIHH1eI9xcG:|cHjvdplt[XSrb36gc4YhTVKEQkKgdoVk\XC2b4Kgb4lv[XOnIHnuJG1FSS2PQjC0OVMh[2WubIOsJGlEPTB;MD6wNFkh|ryP MY[xNFc2OzR5NR?=
human BT474 cells NGjIb|ZRem:uaX\ldoF1cW:wIHHzd4F6 NYnXXnB1OyCmYYnz MXLBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEKWNEe0JINmdGy|IH;2[ZJmgHC{ZYPzbY5oKEWUQnKyJIFnfGW{IEOg[IF6eyCkeTDt[ZRpgWynbnWgZox2\SC|dHHpcolv\yxiRVO1NF0xNjBzIN88US=> NGDhOGwyQTB{OESyOC=>
mouse BAF3 cells MUfGeY5kfGmxbjDhd5NigQ>? M1f4W2lvcGmkaYTpc44hd2ZiQnzrJIV5eHKnc4Pl[EBqdiCvb4Xz[UBDSUZ|IHPlcIx{KGG|c3Xzd4VlKGG|IHP5eI91d3irY3n0fUwhUUN3ME2wMlAzQSEQvF2= NVO1UpVLOTh4NkezNVI>
human HN5 cells MYXQdo9tcW[ncnH0bY9vKGG|c3H5 M3\Nd|Mh\GG7cx?= NXrGdoxXSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDIUlUh[2WubIOgc5ZmemW6cILld5NqdmdiRVfGVkBi\nSncjCzJIRigXNiYomgcYV1cHmuZX7lJIJtfWVic4ThbY5qdmduIFXDOVA:OC5yNTFOwG0> MYmxPVAzQDR{NB?=
human NCI-H1975 cells NEj2VmNRem:uaX\ldoF1cW:wIHHzd4F6 NE\xcFc4OiCq MnLkRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCQQ1mtTFE6PzViY3XscJMhcGG{Yn;ybY5oKEWJRmKgUFg2QFJxVEe5NG0hdXW2YX70JIFnfGW{IEeyJIhzeyCkeTDNWHMh[XO|YYmsJGlEPTB;MD6wOlQh|ryP MUeyNlM{QTN2Mh?=
human A431 cells MUnQdo9tcW[ncnH0bY9vKGG|c3H5 NH7CUpM4OiCq MmjMRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCDNEOxJINmdGy|IH;2[ZJmgHC{ZYPzbY5oKEWJRmKgZYZ1\XJiN{KgbJJ{KGK7IF3UV{Bie3OjeTygTWM2OD1yLkG1JO69VQ>? NU\iOm9EOjJ|M{mzOFI>
human A549 cells M1PhPHBzd2yrZnXyZZRqd25iYYPzZZk> NHznXWY4OiCq M2TuU2FvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iQUW0PUBk\WyuczDlfJBz\XO|aX7nJJdqdGRidInw[UBGT0[UIHPv[ZhxemW|c3nu[{BsNVKjczDteZRidnRiYX\0[ZIhPzJiaILzJIJ6KE2WUzDhd5NigSxiSVO1NF0yNjV7IN88US=> MmTqNlI{Ozl|NEK=
mouse BAF3 cells MVrGeY5kfGmxbjDhd5NigQ>? NVPZeJlkUW6qaXLpeIlwdiCxZjDKRWs{KGW6cILld5Nm\CCrbjDtc5V{\SCEQV[zJINmdGy|IHHzd4V{e2WmIHHzJIN6fG:2b4jpZ4l1ge,:jDDJR|UxRTJizszN MoPtNVg3Pjd|MUK=
human HL7702 cells NHzHTYRRem:uaX\ldoF1cW:wIHHzd4F6 NV\WOYdDPzJiaB?= MXPBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEiON{ewNkBk\WyuczDlfJBz\XO|aX7nJJdqdHRidInw[UBGT0[UIHHmeIVzKDd{IHjyd{BjgSCPVGOgZZN{[XluIFnDOVA:Oi5|IN88US=> NEi5eGMzOjN|OUO0Ni=>
human A431 cells M1Xsb2Z2dmO2aX;uJIF{e2G7 MU[xJO69VQ>? MUGxJIg> NGDWWXVKenKndnXyd4ljdGViaX7obYJqfGmxbjDv[kBGT0[UIHH1eI9xcG:|cHjvdplt[XSrb36gbY4hcHWvYX6gRVQ{OSClZXzsd{BifCBzIIXNJIlv[3WkYYTl[EBnd3JiMTDodkBnd2yub4fl[EBjgSClb33wc5Vv\CC5YYPoJI92fCCvZXHzeZJm\CB3IHjyd{Bxd3O2IFXHSkBi\GSrdHnvckBjgSCZZYP0[ZJvKGKub4T0bY5oKGGwYXz5d4l{ NVi4dnRUOjR7MEC1PVQ>
human LNCaP cells NHW1eYFHfW6ldHnvckBie3OjeR?= NGXRS4UyOCEQvF2= MWCyJIg> NEOyOHJKdmirYnn0bY9vKG:oIHH1eI9xcG:|cHjvdplt[XSrb36gc4YhcW2vdX7vdJJm[2myaYTheIVlKG[uYXeteIFo\2WmIFLtfEBmgHC{ZYPz[YQhcW5iaIXtZY4hVE6FYWCgZ4VtdHNiYYPz[ZN{\WRiYYOgbY5kd3Kyb4LheIlwdiCxZjDbN|JRZUGWUDDheEAyOCC3TTDwdoV1emWjdHXkJIZweiB{IHjyd{Bj\W[xcnWgeJJidnOoZXP0bY9vKGK7IHntcZVvd2Kub4SgZY5idHm|aYO= MnfJNVg3Pjd|MUK=
NCI-H1975 cells NUDvOllPT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= MYq0PEBp M3rqWWlvcGmkaYTpc44hd2ZiRVfGVkBNQDV6Uj;UO|kxVSCvdYThcpQhcW5iaIXtZY4hVkOLLVixPVc2KGOnbHzzJIF{e2W|c3XkJIF{KGe{b4f0bEBqdmirYnn0bY9vKGGodHXyJFQ5KGi{czDifUBOXFRiYYPzZZk> NV;4PGtGOjR7MEC1PVQ>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
pEGFR / EGFR / p-HER2 / HER2 / p-HER3 / HER3 / MUC4 ; 

PubMed: 25686822     


CD18/HPAF and Capan-1 cells were treated with canertinib and afatinib (5 and 1 μM concentration) for 24 hours and control cells were treated with 0.01% DMSO in complete medium. The cell lysates (40μg) were separated by 10% SDS–PAGE and analyzed by Immunoblotting for phospho-EGFR (Y1068), phospho-HER2 (Y1248), phospho-HER3 (Y1289) and total forms of EGFR and HER2 antibodies at indicated concentrations. In parallel, protein lysates were resolved using 2% SDS agarose gel and MUC4 mucin protein was detected by western blot analysis employing anti-MUC4 (8G7) monoclonal antibody. Canertinib and afatinib decreases phosphorylated and total forms of EGFR and HER2, phosphorylated form of HER3, but no change in the expression pattern of blots probed with HER3 and HER4 specific antibodies, between the treatment and control lysates. Canertinib and afatinib significantly decreases MUC4 expression level in both the cell lysates as observed by western blots analysis. The membranes were re-probed with β-actin antibody for loading control.

p-FAK / FAK / p-AKT / AKT ; 

PubMed: 25686822     


Western blot results shows that canertinib and afatinib treatment affects the phosphorylated form of FAK at tyrosine 925 and phospho-AKT at serine 473 with no change in the total FAK and AKT levels when compared to control cells.

25686822
Growth inhibition assay
Cell viability; 

PubMed: 28638122     


Growth control graphs showing effect of selected HER-family TKIs in doubling concentrations on growth of breast cancer cell lines. (a) EGFR reversible inhibitor erlotinib. (b) Dual EGFR/HER2 reversible inhibitor lapatinib. (c) Pan-HER reversible inhibitor sapitinib. (d) Pan-HER irreversible inhibitor canertinib. (e) Pan-HER irreversible inhibitor afatinib. Sulforhodamine B colorimetric assay was used to determine the effect of treatment of breast cancer cell lines with doubling dilutions of HER-family inhibiting TKIs. The irreversible pan-inhibitors (e.g. afatinib, canertinib, neratinib) were consistently more effective than the reversible dual and pan inhibitors (e.g. lapatinib, sapitinib), which were in turn more effective than the reversible EGFR inhibitors (e.g. erlotinib, gefitinib). Each point is a representative of the mean ± SD of triplicate samples.

28638122
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

Kinase Assay:[1]
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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]
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  • 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]
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  • Animal Models: A431 xenografts established in nude mice
  • Formulation: In solution as the isethionate salts
  • 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 powder
in solvent
Synonyms PD183805

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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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID