CP-724714

CP-724714 is a potent, selective inhibitor of HER2/ErbB2 with IC50 of 10 nM, >640-fold selectivity against EGFR, InsR, IRG-1R, PDGFR, VEGFR2, Abl, Src, c-Met etc in cell-free assays. Phase 2.

CP-724714化学構造

CAS No. 537705-08-1

サイズ 価格(税別) 在庫状況
JPY 21900 国内在庫あり
JPY 80000 国内在庫あり

代表番号: 045-509-1970|電子メール:[email protected]
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CP-724714関連製品

シグナル伝達経路

HER2阻害剤の選択性比較

生物活性

製品説明 CP-724714 is a potent, selective inhibitor of HER2/ErbB2 with IC50 of 10 nM, >640-fold selectivity against EGFR, InsR, IRG-1R, PDGFR, VEGFR2, Abl, Src, c-Met etc in cell-free assays. Phase 2.
Targets
HER2/ErbB2 [1]
(Cell-free assay)
10 nM
In Vitro
In vitro CP-724,714 is marked selectively against EGFR with IC50 of 6.4 μM. CP-724,714 is >1,000-fold less potent for IR, IGF-1R, PDGFRβ, VGFR2, abl. Src, c-Met c-jun NH2-terminal kinase (JNK)-2, JNK-3, ZAP-70, cyclin-dependent kinase (CDK)-2, and CDK-5. CP-724,714 potently reduces the EGF-induced autophosphorylation of the chimera containing the erbB2 kinase domain with IC50 of 32 nM, but is markedly less potent against EGFR in transfected NIH3T3 cells. CP-724,714 sensitively inhibits the proliferation of erbB2-amplified cells including BT-474 and SKBR3, with IC50 of 0.25 and 0.95 μM. CP-724,714 induces the accumulation of cells in G1 phase and a marked reduction in S-phase in BT-474 cells at 1 μM. [1] CP-724,714 likely exerts its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. CP-724,714 displays inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, respectively. CP-724,714 inhibits TC transport in membrane vesicles expressing human bile salt export pump with IC50 of 16 μM and inhibits the major efflux transporter in bile canaliculi, MDR1, with IC50 of ~28 μM. [2]
Kinase Assay Kinase assays
Recombinant erbB2 (amino acid residues 675-1255) and EGFR (amino acid residues 668-1211) intracellular domains are expressed in baculovirus-infected Sf9 cells as glutathione S-transferase fusion proteins. The proteins are purified by affinity chromatography on glutathione Sepharose beads for use in the assay. Nunc MaxiSorp 96-well plates are coated by incubation overnight at 37 °C with 100 μL/well of 0.25 mg/mL poly(Glu:Tyr, 4:1), PGT in PBS. Excess PGT is removed by aspiration and the plate is washed 3 times with wash buffer (0.1% Tween 20 in PBS). The kinase reaction is performed in 50 μL of 50 mm HEPES (pH 7.4) containing 125 mm sodium chloride, 10 mm magnesium chloride, 0.1 mm sodium orthovanadate, 1 mm ATP, and ∼15 ng of recombinant protein. Inhibitors in DMSO are added; the final DMSO concentration is 2.5%. Phosphorylation is initiated by addition of ATP and proceeded for 6 min at room temperature, with constant shaking. The kinase reaction is terminated by aspiration of the reaction mixture and washing four times with wash buffer. Phosphorylated PGT is measured after a 25-min incubation with 50 μL/well HRP conjugated-PY54 antiphosphotyrosine antibody, diluted to 0.2 μg/mL in blocking buffer (3% BSA, 0.05% Tween 20 in PBS). Antibody is removed by aspiration and the plate is washed four times with wash buffer. The colorimetric signal is developed by addition of 50 μL/well Tetramethylbenzidine Microwell Peroxidase Substrate and stopped by the addition of 50 μL/well 0.09 m sulfuric acid. The phosphotyrosine product formed is estimated by measurement of absorbance at 450 nm. The signal for controls is typically A0.6–1.2, with essentially no background in wells without ATP, kinase protein, or PGT, and is proportional to the time of incubation for 6 min.
細胞実験 細胞株 ZR-75-30, HCC-1419, MDA-MB-175, BT-474, SKBR3, MDA-MB-361, UACC-812, T-47D, MDA-MB-453, MDA-MB-468, CAMA-1, MDA-MB-157, MCF-7, MDA-MB-435, ZR-75-1, BT-20, and MDA-MB-231.
濃度 0.1 nM - 10 μM.
反応時間 6 to 7 days.
実験の流れ Cells are seeded in duplicate at 5~10 × 103 per well in 24-well plates. The day after plating, CP-724,714 is added by titrating over six or more dilutions from 0.1 nM to 10 μM. Control wells without CP-724,714 are seeded as well. Cells are grown for 6 to 7 days, at which time surviving cells are counted. After trypsinization, cells are placed in isotone solution and counted immediately using a Coulter Z2 particle counter. Growth inhibition is calculated [(1− experimental value / control value) × 100] for each concentration. Dose-response curves are repeated at least twice and averaged. IC50 values are calculated using Calcusyn Software.
実験結果図 Methods Biomarkers 結果図 PMID
Growth inhibition assay Cell viability 27077364
Western blot p-HER2 / HER2 29490608
In Vivo
In Vivo CP-724,714 (25 mg/kg) is rapidly absorbed after p.o. administration and causes reduction of tumor erbB2 receptor phosphorylation after dosing in FRE-erbB2 or BT-474 xenografts. CP-724,714 induces apoptosis in FRE-erbB2 xenograft–bearing (s.c.) mice and shows 50% tumor growth inhibition at 50 mg/kg, without weight loss or mortality. CP-724,714 also has great antitumor activity in MDA-MB-453, MDA-MB-231, LoVo (colon), and Colo-205 (colon) xenografts. Furthermore, CP-724,714 (30 or 100 mg/kg) reduces the extracellular signal–regulated kinase and Akt phosphorylation in BT-474 xenografts. [1]
動物実験 動物モデル FRE-erbB2 BT-474, MDA-MB-453, MDA-MB-231, LoVo (colon), and Colo-205 (colon) xenografts are established in athymic female mice (CD-1 nu/nu).
投与量 ~100 mg/kg.
投与経路 Administered via p.o.

化学情報

分子量 469.53 化学式

C27H27N5O3

CAS No. 537705-08-1 SDF Download CP-724714 SDFをダウンロードする
Smiles CCOC(=O)NCC=CC1=CC2=C(C=C1)N=CN=C2NC3=CC(=C(C=C3)OC4=CN=C(C=C4)C)C
保管

In vitro
Batch:

DMSO : 94 mg/mL ( (200.2 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。)

Ethanol : 94 mg/mL

Water : 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。

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