Dacomitinib

別名:PF299804,PF299

Dacomitinib is a potent, irreversible pan-ErbB inhibitor, mostly to EGFR with IC50 of 6 nM in a cell-free assay. Dacomitinib inhibits ERBB2 and ERBB4 with IC50 of 45.7 nM and 73.7 nM, respectively. Dacomitinib is effective against NSCLCs with EGFR or ERBB2 mutations (resistant to gefitinib) as well as those harboring the EGFR T790M mutation. Dacomitinib inhibits cell growth and induces apoptosis. Phase 2.

Dacomitinib化学構造

CAS No. 1110813-31-4

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 35700 国内在庫あり
JPY 25500 国内在庫あり
JPY 145500 国内在庫あり
JPY 598500 国内在庫なし(納期7~10日)

代表番号: 045-509-1970|電子メール:[email protected]
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文献中Selleckの製品使用例(89)

製品安全説明書

現在のバッチを見る: 純度: 99.81%
99.81

Dacomitinib関連製品

シグナル伝達経路

EGFR阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
NIH/3T3 Function assay 30 mg/kg 2 days In vivo inhibition of full length human ERBB1 autophosphorylation transfected in NIH/3T3 cells implanted in mouse at 30 mg/kg, po qd for 2 days measured 24 hrs post last dose by Western blot analysis 27491023
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 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
PC9 cells Function assay 2 h Inhibition of EGFR exon 19 deletion activating mutant phosphorylation in human PC9 cells after 2 hrs by fluorescence assay, IC50=0.63 nM 23930994
Sf9 Function assay 6 mins Irreversible inhibition of GST-tagged ERBB1 (unknown origin) (Met-668 to Ala-1211 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA, IC50 = 0.006 μM. 27491023
NIH/3T3 Function assay 2 hrs Irreversible inhibition of full length human ERBB1 autophosphorylation transfected in EGF-stimulated mouse NIH/3T3 cells incubated for 2 hrs followed by stimulation with EGF for 10 mins, IC50 = 0.006 μM. 27491023
Sf9 Function assay 6 mins Irreversible inhibition of GST-tagged ERBB2 (unknown origin) (Ile-675 to Val-1256 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA, IC50 = 0.046 μM. 27491023
Sf9 Function assay 6 mins Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA, IC50 = 0.074 μM. 27491023
Sf9 Function assay 30 mins Irreversible inhibition of human recombinant GST-tagged JAK3 expressed in baculovirus infected Sf9 insect cells assessed as reduction in polyglutamic acid-tyrosine phosphorylation after 30 mins by ELISA, IC50 = 3.57 μM. 27491023
NCI-H1819 Antiproliferative assay 72 hrs Antiproliferative activity against human NCI-H1819 cells expressing wild type HER2 incubated for 72 hrs by MTS assay, IC50 = 0.029 μM. 28754471
NCI-H1975 Antiproliferative assay 72 hrs Antiproliferative activity against human NCI-H1975 cells expressing EGFR T790M/L858R mutant incubated for 72 hrs by MTS assay, IC50 = 0.44 μM. 28754471
human NCI-H1975 cells Proliferation assay Antiproliferative activity against human NCI-H1975 cells assessed as growth inhibition, GI50=0.1233 μM 26310890
insect cells Function assay Inhibition of GST-tagged human EGFR catalytic domain expressed in insect cells, IC50 = 0.006 μM. 28754471
insect cells Function assay Inhibition of GST-tagged human HER2 catalytic domain expressed in insect cells, IC50 = 0.0457 μM. 28754471
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生物活性

製品説明 Dacomitinib is a potent, irreversible pan-ErbB inhibitor, mostly to EGFR with IC50 of 6 nM in a cell-free assay. Dacomitinib inhibits ERBB2 and ERBB4 with IC50 of 45.7 nM and 73.7 nM, respectively. Dacomitinib is effective against NSCLCs with EGFR or ERBB2 mutations (resistant to gefitinib) as well as those harboring the EGFR T790M mutation. Dacomitinib inhibits cell growth and induces apoptosis. Phase 2.
Targets
EGFR [1]
(Cell-free assay)
ErbB2 [1]
(Cell-free assay)
ErbB4 [1]
(Cell-free assay)
6.0 nM 45.7 nM 73.7 nM
In Vitro
In vitro

PF299804 is a specific inhibitor of the ERBB family of kinases. PF299804 inhibits EGFR signaling and induces apoptosis in the EGFR T790M-containing H3255 GR cell line. PF299804 is effective in -sensitive and NSCLC cell lines. PF299804 inhibits the growth of H3255 and HCC827 cells engineered to express EGFR T790M. PF299804 inhibits EGFR phosphorylation in the presence of the T790M mutation. [1] PF-299804 is believed to irreversibly inhibit ERBB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of ERBB family members. [2] PF299804 shows significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it has lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including BIBW-2992, and CI-1033. PF299804 induces apoptosis and G1 arrest and inhibits phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal-regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF299804 also blocks EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. [3] A recent research uses forty-seven human breast cancer and immortalized breast epithelial lines to evaluate the inhibition effects of PF299804, the results indicate PF299804 preferentially inhibits growth of HER-2-amplified breast cancer cell lines than nonamplified lines (RR = 3.39, p < 0.0001). PF299804 reduces the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. PF299804 exerts its anti-proliferative effect through a combined G0/G1 arrest and an induction of apoptosis. [4]

Kinase Assay ELISA-Based ERBB Kinase Assay
The ERBB1, ERBB 2, and ERBB4 cytoplasmic fusion proteins are made by cloning the ERBB1 sequence (Met-668 to Ala-1211), ERBB2 (Ile-675 to Val-1256), and ERBB4 sequence (Gly-259 to Gly-690) into the baculoviral vector pFastBac using PCR. Proteins are expressed in baculovirusinfected Sf9 insect cells as GST fusion proteins. The proteins are purified by affinity chromatography using glutathione sepharose beads. Inhibition of ERBB tyrosine kinase activity is assessed using an ELISA-based receptor tyrosine kinase assay. Kinase reactions (50 mM HEPES, pH 7.4, 125 mM NaCl, 10 mM MgCl2, 100 μM sodium orthovanadate, 2 mM dithiothreitol, 20 μM ATP, PF299804 or vehicle control, and 1-5 nM GST-erbB per 50 μL of reaction mixture) are run in 96-well plates coated with 0.25 mg/mL poly-Glu-Tyr. The reactions are incubated for 6 minutes at room temperature while being shaken. Kinase reactions are stopped by removal of the reaction mixture, and then the wells are washed with wash buffer (0.1% Tween 20 in PBS). Phosphorylated tyrosine residues are detected by adding 0.2 μg/mL antiphosphotyrosine antibody (Oncogene Ab-4; 50 μL/well) coupled to horseradish peroxidase (HRP) diluted in PBS containing 3% BSA and 0.05% Tween 20 for 25 minutes while being shaken at room temperature. The antibody is removed, and plates are washed in wash buffer. HRP substrate (SureBlue3,3,5,5-tetramethyl benzidine or TMB) is added (50 μL per well) and incubated for 10-20 minutes while it is shaken at room temperature. The TMB reaction is stopped with the addition of 50 μL of stop solution (0.09 N H2SO4). The signal is quantified by measuring absorbance at 450 nm. IC50 values are determined for PF299804 using the median effect method.
細胞実験 細胞株 Various NSCLC cell lines
濃度 0-20 nM
反応時間 72 hours
実験の流れ

Growth and inhibition of growth is assessed by 5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. This assay, a colorimetric method fordetermining the number of viable cells, is based on the bioreduction of MTS by cells to a formazan product that is soluble in cell culture medium, can be detected spectrophotometrically. The cells are exposed totreatment for 72 hours, and the number of cells used per experiment is determined empirically. All experimental points are set up in 6 to 12 wells, and all experiments are repeated at least thrice. The data are graphically displayed using GraphPad Prism version 3.00 for Windows (GraphPad Software). The curves are fitted using a nonlinear regression model with a sigmoidal dose response.

実験結果図 Methods Biomarkers 結果図 PMID
Western blot pEGFR / EGFR / pERK / ERK / pAKT / AKT / p-mTOR / mTOR / pSTAT3 / STAT3 24853121
Immunofluorescence LC3 28366635
Growth inhibition assay Cell viability 28363995
In Vivo
In Vivo

Orally administered PF299804 effectively inhibits growth of HCC827 Del/T790M xenografts. [1] Low oral administration of PF-299804 (15mg/kg) causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/ or overexpress ERBB family members or contain the double mutation (L858R/T790M) in ERBB1 (EGFR). [2]

動物実験 動物モデル HCC827-GFP or HCC827-Del/T790M lung cancer cells (in 0.2 mL of PBS) are inoculated s.c. into the lower-right quadrant of the flank of nude mice
投与量 10 mg/kg
投与経路 Administered via oral gavage
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT06075615 Not yet recruiting
Carcinoma Non-Small-Cell Lung
Pfizer
September 1 2024 --
NCT06321510 Not yet recruiting
Lung Cancer
Pfizer
April 1 2024 --
NCT04609319 Active not recruiting
Lung Cancer
Pfizer
January 23 2021 --
NCT03865446 Completed
Severe Hepatic Impairment
Pfizer
April 5 2019 Phase 1
NCT02382796 Completed
NSCLC
Pfizer
July 10 2015 Phase 2
NCT02268747 Unknown status
Skin Squamous Cell Cancer
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
November 2014 Phase 2

化学情報

分子量 469.94 化学式

C24H25ClFN5O2

CAS No. 1110813-31-4 SDF Download Dacomitinib SDFをダウンロードする
Smiles COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)NC(=O)C=CCN4CCCCC4
保管

In vitro
Batch:

DMSO : 12.5 mg/mL ( (26.59 mM); 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ1:実験データを入力してください。(実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します)

mg/kg g μL

ステップ2:投与溶媒の組成を入力してください。(ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果:

投与溶媒濃度: mg/ml;

DMSOストック溶液調製方法: mg 試薬を μL DMSOに溶解する(濃度 mg/mL, 注:濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法:Take μL DMSOストック溶液に μL PEG300,を加え、完全溶解後μL Tween 80,を加えて完全溶解させた後 μL ddH2O,を加え完全に溶解させます。

投与溶媒調製方法:μL DMSOストック溶液に μL Corn oil,を加え、完全溶解。

注意:1.ストック溶液に沈殿、混濁などがないことをご確認ください;
2.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

技術サポート

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Handling Instructions

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よくある質問(FAQ)

質問1:
I would like to know whether the in vivo formulation you recommend is suitable for oral administration?

回答
S2727 in 1% DMSO+30% polyethylene glycol+1% Tween 80 at 10mg/ml is a homogeneous suspension, and it was fine for oral gavage. When preparing the solution, please dissolve the compound in DMSO clearly first. If it dissolves not readily, please sonicate and warm it at about 45-50℃ for a while to help dissolving. Then add PEG 300 and Tween 80. After they mixed well, dilute with water. Then it will become a homogeneous suspension.

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