产品说明书

Dacomitinib

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Chemical Structure| 1110813-31-4 同义名 : PF-00299804;PF-299804;PF299
CAS号 : 1110813-31-4
货号 : A119719
分子式 : C24H25ClFN5O2
纯度 : 98%
分子量 : 469.939
MDL号 : -
存储条件：

粉末 Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 40 mg/mL(85.12 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 1 mg/mL clear

PO 0.5% CMC-Na 45 mg/mL suspension

生物活性
靶点

  • EGFR/ErbB1

    EGFR, IC50:6.0 nM

  • HER2/ErbB2

    ErbB2, IC50:45.7 nM

  • ErbB4

    ErbB4, IC50:73.7 nM
描述 EGFR (epidermal growth factor receptor) family consists of four members that belong to the ErbB lineage of proteins (ErbB1 - 4) with an external domain that binds activating ligands, such as EGF, and is overexpressed in a significant percentage of carcinomas and contributes to the malignant phenotype. Upon activation, EGFR phosphorylates both the receptor itself and a variety of “effector” protein. Dacomitinib is an irreversible pan-ERBB inhibitor with IC50 values of 6 nM，45.7 nM and 73.3 nM for EGFR, ERBB2 and ERBB4 (performed by in vitro kinase assays), respectively. Dacomitinib at concentration of 1 μM led to complete inhibition of EGFR, ERBB3 and Akt phosphorylation, as well as substantial apoptosis, in EGFR T790M–containing H3255 GR cell line. Dacomitinib inhibited both wild-type and mutant ERBB2, but showed more effective on mutant EGFR than gefitinib at similar concentrations. Dacomitinib was highly effective in a xenograft (HCC827 Del/T790M) model of T790M-mediated acquired resistance to gefitinib at dose of 10 mg/kg/d by daily oral gavage[1].
作用机制 Dacomitinib can bind with the ATP site and make a covalent modification of nucleophilic cysteine residues in the catalytic domains of ERBB[2].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human LoVo cells Function assay 2 h Inhibition of wild type EGFR phosphorylation in human LoVo cells after 2 hrs by fluorescence assay, IC50=0.011 μM 23930994
human NCI-H1975 cells Function assay 2 h Inhibition of EGFR L858R/T970M double mutant phosphorylation in human NCI-H1975 cells after 2 hrs by fluorescence assay, IC50=0.042 μM 23930994
human NCI-H1975 cells Proliferation assay Antiproliferative activity against human NCI-H1975 cells assessed as growth inhibition, GI50=0.1233 μM 26310890
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.13mL

0.43mL

0.21mL

10.64mL

2.13mL

1.06mL

21.28mL

4.26mL

2.13mL
参考文献

[1]Engelman JA, Zejnullahu K, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007 Dec 15;67(24):11924-32.

[2]Gonzales AJ, Hook KE, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2008 Jul;7(7):1880-9.

[3]Pharmacodynamic reports of dacomitinib