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Poziotinib

別名：HM781-36B, NOV120101

Poziotinib is an irreversible pan-HER inhibitor with IC50 of 3.2 nM, 5.3 nM and 23.5 nM for HER1, HER2, and HER4, respectively. Poziotinib also induces apoptosis and G1 cell cycle arrest. Phase 2.

Poziotinib化学構造

CAS No. 1092364-38-9

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 34000 国内在庫あり
JPY 22000 国内在庫あり
JPY 71500 国内在庫あり
JPY 149500 国内在庫あり
JPY 448500 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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製品安全説明書

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Poziotinib関連製品

シグナル伝達経路

EGFR Signaling Pathways

EGFR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
A431 Antiproliferative assay 72 hrs Antiproliferative activity against human A431 cells expressing wild type EGFR incubated for 72 hrs by MTS assay, IC50 = 0.0009 μM. 28754471
SKBR3 Antiproliferative assay 72 hrs Antiproliferative activity against human SKBR3 cells expressing wild type HER2 incubated for 72 hrs by MTS assay, IC50 = 0.001 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 = 0.0057 μM. 28754471
HS27 Antiproliferative assay 72 hrs Antiproliferative activity against human HS27 cells expressing wild type HER2 incubated for 72 hrs by MTS assay, GI50 = 3.83 μM. 28754471
SKBR3 Anticancer assay 72 hrs Anticancer activity against Erb-B2 overexpressing human SKBR3 cells assessed as cell growth inhibition after 72 hrs by SRB assay, ID50 = 0.0003 μM. ChEMBL
A431 Anticancer assay 72 hrs Anticancer activity against EGFR overexpressing human A431 cells assessed as cell growth inhibition after 72 hrs by SRB assay, ID50 = 0.0004 μM. ChEMBL
Sf21 Function assay 10 mins Inhibition of N-terminal GST-tagged human EGFR (696 to end residues) expressed in baculovirus infected Sf21 cells using poly (Glu,Tyr)4:1 as substrate preincubated for 10 mins followed by substrate addition measured after 1 hr by fluorescence polarization, IC50 = 0.0013 μM. ChEMBL
NCI-H1975 Anticancer assay 48 hrs Anticancer activity against human NCI-H1975 cells assessed as cell growth inhibition after 48 hrs by celltiter one shot solution assay, IC50 = 0.0027 μM. ChEMBL
Sf21 Function assay 10 mins Inhibition of N-terminal GST-tagged recombinant human EGFR T790M mutant expressed in baculovirus infected Sf21 cells using poly (Glu,Tyr)4:1 as substrate preincubated for 10 mins followed by substrate addition measured after 1 hr by fluorescence polarizat, IC50 = 0.0044 μM. ChEMBL
Ba/F3 Function assay Inhibition of human EGFR T790M/L858R mutant expressed in mouse Ba/F3 cells, IC50 = 0.0022 μM. 28754471
insect cells Function assay Inhibition of GST-tagged human EGFR catalytic domain expressed in insect cells, IC50 = 0.0032 μM. 28754471
Ba/F3 Function assay Inhibition of human EGFR T790M mutant expressed in mouse Ba/F3 cells, IC50 = 0.0042 μM. 28754471
insect cells Function assay Inhibition of GST-tagged human HER2 catalytic domain expressed in insect cells, IC50 = 0.0053 μM. 28754471
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生物活性

製品説明 Poziotinib is an irreversible pan-HER inhibitor with IC50 of 3.2 nM, 5.3 nM and 23.5 nM for HER1, HER2, and HER4, respectively. Poziotinib also induces apoptosis and G1 cell cycle arrest. Phase 2.
Targets
HER1 [1]
(Cell-free assay)		 HER2 [1]
(Cell-free assay)		 HER4 [1]
(Cell-free assay)
3.2 nM 5.3 nM 23.5 nM
In Vitro
In vitro Poziotinib specifically inhibits the cell growth in HER2 amplified gastric cancer cells, and inhibits the phosphorylation of EGFR and key components of downstream signaling cascades such as STAT3, AKT and ERK. Poziotinib also induces apoptosis and G1 cell cycle arrest by activating the mitochondrial pathway in HER2 amplified gastric cancer cells. Furthermore, Poziotinib also exerts synergistic effects with chemotherapeutic agents in both HER2 amplified and HER2 non-amplified gastric cancer cells. [1]
Kinase Assay Enzyme activity assay
To determine the IC50 values of HM781-36B for kinase inhibition, enzymes of EGFR, HER2, and HER4 are expressed as recombinant proteins in Sf9 insect cells. Enzyme selectivity screening is then performed using a tyrosine kinase assay kit. Briefly, the reactions are performed in 96 well polystyrene round-bottomed plates containing kinase buffer composed of 100 mM HEPES (pH 7.4), 25 mM MgCl2, 10 mM MnCl2 and 250 μM Na3VO4. The reactions are initiated by the addition of 100 ng/assay enzyme, 100 μM ATP, and 10 ng/mL poly(Glu, Tyr). After 1 h of incubation at room temperature, the reactions are terminated by adding 6 mM EDTA solution and then anti-phosphotyrosine antibody, PTK Green Tracer, and FP dilution buffer mixtures. The fluorescence polarization values are then measured after 30 min at room temperature using a Victor3 microplate reader. Finally, the IC50 values were calculated using the following equation: Y = bottom + (top–bottom)/(1 + 10(X-logIC50)).
細胞実験 細胞株 Gastric cancer cell lines (SNU-1, 5, 16, 216, 484, 601, 620, 638, 668, 719, N87 and AGS)
濃度 ~10 μM
反応時間 72 hours
実験の流れ Viable cell growth is determined by an MTT reduction assay. Briefly, all cell lines are seeded at a density of 3 × 103 per well in 96-well culture plates and then incubated at 37 °C for 24 h. The cells are then treated with 0.001, 0.01, 0.1, or 10 μM of HM781-36B. Three days later, 50 μg of MTT are added to each well and the samples are then incubated for 4 h to reduce the dye. Next, the samples are treated with DMSO, after which the absorbance of the converted dye in the living cells is measured at a wavelength of 540 nm. Six replicate wells are used for each analysis, and at least three independent experiments are conducted. Data points shown represent the mean while bars represent the SE.
実験結果図 Methods Biomarkers 結果図 PMID
Western blot Cleaved caspase-3 / Cleaved caspase-9 / PARP / Bcl-2 pEGFR / EGFR / pHER2 / HER2 / BMX / pERK / ERK / pAKT / AKT 25761479
Growth inhibition assay Cell viability 25761479
In Vivo
In Vivo In nude mice bearing N87 human gastric cancer xenografts, Poziotinib (0.5 mg/kg p.o.) alone significantly inhibits the growth of tumors, and coadministraion of Poziotinib and 5-FU causes more effective tumor inhibition. [1] In addition, HM781-36B shows excellent antitumor activity in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. [2]
動物実験 動物モデル BALB/c athymic nude mice bearing N87 xenografts
投与量 0.5 mg/kg daily
投与経路 p.o.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT04436562 Completed
Healthy
Spectrum Pharmaceuticals Inc
 May 29 2020 Phase 1
NCT03804515 Terminated
Solid Tumor
Spectrum Pharmaceuticals Inc
 June 25 2019 Phase 1

化学情報

分子量 491.34 化学式

C23H21Cl2FN4O3
CAS No. 1092364-38-9 SDF Download Poziotinib SDFをダウンロードする
Smiles COC1=C(C=C2C(=C1)N=CN=C2NC3=C(C(=C(C=C3)Cl)Cl)F)OC4CCN(CC4)C(=O)C=C
保管

In vitro
Batch:

DMSO : 98 mg/mL ( (199.45 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 匹

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。

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