Canertinib (CI-1033)

製品コードS1019 バッチS101903

印刷

化学情報

Chemical Structure Synonyms PD183805 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C24H25ClFN5O3
分子量 485.94 CAS No. 267243-28-7
Solubility (25°C)* 体外 Ethanol 9 mg/mL (18.52 mM)
DMSO 2 mg/mL (4.11 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 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.
in vitro

Canertinib (CI-1033) shows excellent potency for irreversible inhibition of erbB2 autophosphorylation in MDA-MB 453 cells. It also shows high permeability in Caco-2 cells. [1] This compound alone significantly suppresses constitutively activated Akt and MAP kinase, and in combination inhibits Akt and prevents increased levels of MAPK phosphorylation. It 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. It shows high levels of inhibition in A431 cells expressing EGFR with IC50 of 7.4 nM. The compound suppresses heregulin-stimulated tyrosine phosphorylation of erbB2, erbB3 and erbB4 with IC50 of 5, 14 and 10 nM, respectively, and also inhibits expression of pp62c-fos in response to heregulin. [3] It 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 this compound at a concentration of 3 μM or higher. It 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

Canertinib (CI-1033) shows impressive activity against A431 xenografts in nude mice at 5 mg/kg of body weight. [1] It achieves a high degree of tumor regressions in H125 xenograft models at 20 to 80 mg/kg/d. [3] Oral administration of this compound causes a marked inhibition of growth in TT, TE6 and TE10 xenografts in nude mice, without animal death and <10% weight loss. [6]
特徴 First kinase inhibitor to show irreversible activity and to have entered clinical trials (serving as a template for further development).

プロトコル(参考用のみ)

キナーゼアッセイ 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, 10 μM the ATP containing 0.5 mCi of [32P]ATP, 20 mg of polyglutamic acid/tyrosine, 10 ng of EGFR tyrosine kinase, and appropriate dilutions of Canertinib (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.
細胞アッセイ 細胞株 TT, TE2, TE6 and TE10 cells
濃度 0.1-5.0 nM
反応時間 1, 3, 5 and 7 days
実験の流れ

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 Canertinib (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.
動物実験 動物モデル A431 xenografts established in nude mice
投薬量 ~18 mg/kg
投与方法 Administered orally

参考

  • https://pubmed.ncbi.nlm.nih.gov/10753475/
  • https://pubmed.ncbi.nlm.nih.gov/11278435/
  • https://pubmed.ncbi.nlm.nih.gov/11706399/
  • https://pubmed.ncbi.nlm.nih.gov/12006493/
  • https://pubmed.ncbi.nlm.nih.gov/16007579/
  • https://pubmed.ncbi.nlm.nih.gov/17342332/
  • https://pubmed.ncbi.nlm.nih.gov/11212277/

カスタマーフィードバック

Data from [Carcinogenesis, 2010, 31, 1948–1955]

Data from [Carcinogenesis, 2010, 31, 1948–1955]

Data from [Cell Cycle, 2009, 13, 2050-2056]

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Acidosis-induced activation of distal nephron principal cells triggers Gdf15 secretion and adaptive proliferation of intercalated cells [ Acta Physiol (Oxf), 2021, 10.1111/apha.13661] PubMed: 33840159
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長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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