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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  • (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.

    Carcinogenesis 2010 31, 1948–1955. Canertinib (CI-1033) purchased from Selleck.

    LNCaP-AI cells were starved in 1% stripped medium for 24 h. The cells were then treated with Erlotinib (20 μM), Gefitinib (20 μM), Lapatinib (20 μM), CI-1033 (8 μM), LY294002 (20 μM) and Bortezomib (20 μM) 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.

     

     

    Carcinogenesis 2010 31, 1948–1955. Canertinib (CI-1033) purchased from Selleck.

  •  

    Involvement of PKC δ in the reactivation of EGFR family members and downstream Akt and Erk signaling following prolonged c-Met TKI treatment. (B) H1993 cells were treated with SU1274 for 4 h (lane 2) or 48 h (lane 3–6). CI-1033 (1.5 μM, lane 4), rottlerin (10 μM, lane 5), or GO6976 (10 μM, lane 6) were added 4 hours before the cells were harvested. Untreated (lane 1) or treated cells were analyzed by immunobloting with the indicated antibodies.

    Cell Cycle 2009 13, 2050-2056. Canertinib (CI-1033) purchased from Selleck.

    Involvement of PKC δ in the reactivation of EGFR family members and downstream Akt and Erk signaling following prolonged c-Met TKI treatment. H1993 cells were incubated continuously with DMSO (◆), CI-1033 (1.5 μM), SU11274 (2.5 μM, ▲), 17-AAG (0.5 μM, *), SU11274 and CI-1033 (□), or SU11274 and rottlerin (1 μM, △). Cell density was monitored for 6 consecutive days by MTS assay. Each point represents the mean of 4 determinations; error bars, SD.

    Cell Cycle 2009 13, 2050-2056. Canertinib (CI-1033) purchased from Selleck.

  • 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

     

     

    Dr. Zhang of Tianjin Medical University. Canertinib (CI-1033) purchased from Selleck.

    H1975 cells were pretreated with 10nm EGF for 15 min and then treated with the indicated concentrations of  CI-1033 for 2 hours.

     

     

    Dr. Kian Kani of Cedars-Sinai Medical Center. Canertinib (CI-1033) purchased from Selleck.

  • A431 80% confluent 10cm plates, 24hour FBS starvation,  then treatment with compounds at 10nM for 30mins, followed by 5 minutes of 0.05ug/ml of EGF.  Pellet was sonicated (setting 5, 5 seconds, twice), then quenched with 2XGSB.  Loaded 10ul on AnyKD BioRad gel (20mins at 250V), transfered with BioRad Turbo system for 15 minutes (1.5A, 25V).  Blocked with 5% milk for 1 hour at RT.  Rocked overnight at 1:1000 in 5% BSA with primary Abs; Anti-rabbit secondary Ab at 1:2000 in 5% milk for 1 hour, developed with Thermo Femto Kit.

    Canertinib (CI-1033) purchased from Selleck.

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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 MnnRVJJwdGmoZYLheIlwdiCjc4PhfS=> MYC3NkBp M{PuWmFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iSFPDPFI4KGOnbHzzJIhiemKxcnnu[{BGT0[UIHTlcEBGPzR4LVG3OVAhdXW2YX70JIFnfGW{IEeyJIhzeyCkeTDNWHMh[XO|YYmsJGlEPTB;MD6wNFEh|ryP MV6yNlM{QTN2Mh?=
A431 cells NYi5RnpMTnWwY4Tpc44h[XO|YYm= MV\Jcohq[mm2aX;uJI9nKEWJRj3zeIlufWyjdHXkJIF2fG:yaH;zdIhwenmuYYTpc44hd2ZiRVfGVkBmdnq7bXWgbY4hSTR|MTDj[YxteyCmZYTlZ5Rm\CCkeTDpcY12dm:kbH;0eIlv\yxiSVO1NF0xNjByN{Sg{txO MVyxNFc2OzR5NR?=
MDA-MB 453 cells NUS3[XhxTnWwY4Tpc44h[XO|YYm= NITmO4FKdmirYnn0bY9vKG:oIHH1eI9xcG:|cHjvdplt[XSrb36gc4YhTVKEQkKgdoVk\XC2b4Kgb4lv[XOnIHnuJG1FSS2PQjC0OVMh[2WubIOsJGlEPTB;MD6wNFkh|ryP MmW4NVA4PTN2N{W=
human BT474 cells NUPiVmhqWHKxbHnm[ZJifGmxbjDhd5NigQ>? MYezJIRigXN? Ml:4RY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCEVES3OEBk\WyuczDveoVz\XiycnXzd4lv\yCHUlLiNkBi\nSncjCzJIRigXNiYomgcYV1cHmuZX7lJIJtfWVic4ThbY5qdmduIFXDOVA:OC5yMTFOwG0> M1L4ZVE6ODJ6NEK0
mouse BAF3 cells MV\GeY5kfGmxbjDhd5NigQ>? Ml24TY5pcWKrdHnvckBw\iCEbHug[ZhxemW|c3XkJIlvKG2xdYPlJGJCTjNiY3XscJMh[XO|ZYPz[YQh[XNiY4n0c5RwgGmlaYT5MEBKSzVyPUCuNFI6KM7:TR?= NXTlNXo{OTh4NkezNVI>
human HN5 cells NYDqNpp[WHKxbHnm[ZJifGmxbjDhd5NigQ>? NUnnOGh7OyCmYYnz MVHBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEiQNTDj[YxteyCxdnXy[ZhxemW|c3nu[{BGT0[UIHHmeIVzKDNiZHH5d{BjgSCvZYTofYxmdmViYnz1[UB{fGGrbnnu[{whTUN3ME2wMlA2KM7:TR?= NX\KSpRxOTlyMki0NlQ>
human NCI-H1975 cells MXXQdo9tcW[ncnH0bY9vKGG|c3H5 Mo\sO|IhcA>? MkTiRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCQQ1mtTFE6PzViY3XscJMhcGG{Yn;ybY5oKEWJRmKgUFg2QFJxVEe5NG0hdXW2YX70JIFnfGW{IEeyJIhzeyCkeTDNWHMh[XO|YYmsJGlEPTB;MD6wOlQh|ryP MmP1NlI{Ozl|NEK=
human A431 cells NH;wWJBRem:uaX\ldoF1cW:wIHHzd4F6 NV30bI17PzJiaB?= M{HNS2FvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iQUSzNUBk\WyuczDveoVz\XiycnXzd4lv\yCHR1\SJIFnfGW{IEeyJIhzeyCkeTDNWHMh[XO|YYmsJGlEPTB;MD6xOUDPxE1? NEnPSlUzOjN|OUO0Ni=>
human A549 cells MVjQdo9tcW[ncnH0bY9vKGG|c3H5 MmfXO|IhcA>? MV;BcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEF3NEmgZ4VtdHNiZYjwdoV{e2mwZzD3bYxlKHS7cHWgSWdHWiClb3X4dJJme3Orbnegb{1T[XNibYX0ZY51KGGodHXyJFczKGi{czDifUBOXFNiYYPzZZktKEmFNUC9NU42QSEQvF2= NF;KXWUzOjN|OUO0Ni=>
mouse BAF3 cells M3ztT2Z2dmO2aX;uJIF{e2G7 MYDJcohq[mm2aX;uJI9nKEqDS{Og[ZhxemW|c3XkJIlvKG2xdYPlJGJCTjNiY3XscJMh[XO|ZYPz[YQh[XNiY4n0c5RwgGmlaYT589yNKEmFNUC9NkDPxE1? MmHBNVg3Pjd|MUK=
human HL7702 cells MYrQdo9tcW[ncnH0bY9vKGG|c3H5 M2LxW|czKGh? MmTPRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCKTEe3NFIh[2WubIOg[ZhxemW|c3nu[{B4cWy2IIT5dIUhTUeIUjDh[pRmeiB5MjDodpMh[nliTWTTJIF{e2G7LDDJR|UxRTJwMzFOwG0> M4\KUFIzOzN7M{Sy
human A431 cells NVzwfnd5TnWwY4Tpc44h[XO|YYm= NEjlVFkyKM7:TR?= M3vkc|EhcA>? M1:1c2lzemW4ZYLzbYJt\SCrbnjpZol1cW:wIH;mJGVITlJiYYX0c5Bpd3OyaH;yfYxifGmxbjDpckBpfW2jbjDBOFMyKGOnbHzzJIF1KDFidV2gbY5kfWKjdHXkJIZweiBzIHjyJIZwdGyxd3XkJIJ6KGOxbYDveY5lKHejc3igc5V1KG2nYYP1doVlKDViaILzJJBwe3RiRVfGJIFl\Gm2aX;uJIJ6KFenc4Tldo4h[myxdITpcoch[W6jbInzbZM> M{DqcFI1QTByNUm0
human LNCaP cells MkLiSpVv[3Srb36gZZN{[Xl? M1rDWFExKM7:TR?= NUKzN257OiCq NFj5NJZKdmirYnn0bY9vKG:oIHH1eI9xcG:|cHjvdplt[XSrb36gc4YhcW2vdX7vdJJm[2myaYTheIVlKG[uYXeteIFo\2WmIFLtfEBmgHC{ZYPz[YQhcW5iaIXtZY4hVE6FYWCgZ4VtdHNiYYPz[ZN{\WRiYYOgbY5kd3Kyb4LheIlwdiCxZjDbN|JRZUGWUDDheEAyOCC3TTDwdoV1emWjdHXkJIZweiB{IHjyd{Bj\W[xcnWgeJJidnOoZXP0bY9vKGK7IHntcZVvd2Kub4SgZY5idHm|aYO= M4XyRlE5PjZ5M{Gy
NCI-H1975 cells NX3QSZkyT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= MY[0PEBp M{LmOmlvcGmkaYTpc44hd2ZiRVfGVkBNQDV6Uj;UO|kxVSCvdYThcpQhcW5iaIXtZY4hVkOLLVixPVc2KGOnbHzzJIF{e2W|c3XkJIF{KGe{b4f0bEBqdmirYnn0bY9vKGGodHXyJFQ5KGi{czDifUBOXFRiYYPzZZk> NGDRdGIzPDlyMEW5OC=>

... Click to View More Cell Line Experimental Data

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]
+ Expand

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]
+ Expand
  • 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]
+ Expand
  • 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 slightly soluble or insoluble
In vivo Add solvents individually and in order:
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.

Chemical Information

Molecular Weight 485.94
Formula

C24H25ClFN5O3

CAS No. 267243-28-7
Storage powder
in solvent
Synonyms PD183805

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00050830 Completed Lung Neoplasms Pfizer January 2003 Phase 2
NCT00174356 Completed Carcinoma, Non-Small Cell Lung Pfizer December 2002 Phase 1
NCT00051051 Completed Breast Neoplasms Pfizer December 2002 Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID