Pimasertib (AS-703026)

別名:MSC1936369B, SAR 245509

Pimasertib (AS-703026, MSC1936369B, SAR 245509) is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 with IC50 of 5 nM-2 μM in MM cell lines. Phase 2.

Pimasertib (AS-703026)化学構造

CAS No. 1236699-92-5

サイズ 価格(税別) 在庫状況
JPY 22000 国内在庫あり
JPY 29500 国内在庫あり
JPY 40500 国内在庫あり
JPY 448500 国内在庫あり

代表番号: 045-509-1970|電子メール:[email protected]
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Pimasertib (AS-703026)関連製品

シグナル伝達経路

MEK阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
human COLO205 cells Function assay Inhibition of MEK1 in human COLO205 cells, IC50=0.00181 μM 24755426
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生物活性

製品説明 Pimasertib (AS-703026, MSC1936369B, SAR 245509) is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 with IC50 of 5 nM-2 μM in MM cell lines. Phase 2.
特性 A novel, highly selective and potent allosteric inhibitor of MEK1/2.
Targets
MEK1/2 (MM cell line) [1]
(Cell-free assay)
5 nM-2 μM
In Vitro
In vitro AS703026 is a novel, selective, orally bioavailable MEK1/2 inhibitor that binds to the distinctive MEK allosteric site and therefore exhibits exquisite kinase selectivity. AS703026 inhibits growth and survival of human multiple myeloma (MM) cells, including U266 and INA-6, with IC50 of 5 nM and 11 nM, respectively. Such an inhibitory effect by AS703026 is mediated by G0-G1 cell cycle arrest and is accompanied by reduced expresson of the MAF oncogene. AS703026 further induces apoptosis via caspase-3 and PARP cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). [1] AS703026 may be an effective therapy in colorectal cancer caused by K-Ras mutation. AS703026 (10 μM) effectively inhibits the ERK pathway, proliferation, and transformation in human DLD-1 colorectal cancer cells what carry a mutant allele of K-Ras (D-MUT). [2]
Kinase Assay MEK1 enzyme assays
AS703026 is dissolved in 2.5% DMSO. Activated diphosphorylated MEK (pp-MEK) assays contained 40 μM 33P-γATP (AppKm 8.5 μM), 0.5 nM human-activated MEK1 or MEK2, 1 μM kinase-dead ERK2 (AppKm 0.73 μM). All assays are done in buffer containing 20 mM HEPES (pH 7.2), 5 mM 2-mercaptoethanol, 0.15 mg/mL BSA, and 10 mM MgCl2. The final concentration of 33P- ATP is 0.02 μCi/μL for all the assays. pp-MEK kinase reactions are stopped after 40 min by transferring 30 μL of reaction mixture to Durapore 0.45-μm filters plates containing 12.5% TCA. Filters are dried and read with liquid scintilant on a TopCount. Concentration response data are analyzed for IC50. 0.2 nM recombinant human MEK1 or MEK2 is preincubated with vehicle or with AS703026 for 40 minutes in reaction buffer to determine IC50 of initially unphosphorylated MEK (u-MEK). Phosphorylation/activation is initiated by the addition of a final concentration of 20 nM final B-RafV600E and 30 μM final ATP for 10 min. B-Raf activity is then quenched by addition of the B-Raf inhibitor SB590885 (final concentration 100 nM), and MEK kinase activity is assayed by the addition of 1 μM KD-ERK2 and 0.02 μCi/μL 33P-ATP in reaction buffer. The kinase reactions are stopped after 90 min by transferring 30μL of reaction mixture to a Durapore filter plate, and read as above.
細胞実験 細胞株 U266 and INA-6 cells
濃度 2 nM - 20 μM (stock: 10 mM in DMSO)
反応時間 48 hours
実験の流れ Cytotoxicity assays for AS703026 are assessed by measuring both [3H]thymidine incorporation and MTT dye absorbance. Cells (1 × 104 per well) are cultured in 96-well plates for 3 days. For the [3H]thymidine incorporation assay, cells are pulsed with 18.5 kBq/well [3H]thymidine for 6 hours, harvested onto glass fibre filters, and counted in a β-scintillation counter. Cell cycle analysis is assessed by propidium iodide (PI) staining using flow cytometry. AS703026-induced apoptosis is determined by annexin-V/PI staining and flow cytometric data analysis.
実験結果図 Methods Biomarkers 結果図 PMID
Western blot p-ERK / ERK 27102436
Growth inhibition assay Cell viability 26381508
In Vivo
In Vivo AS703026 (15 and 30 mg/kg) significantly inhibits tumor growth in a human plasmacytoma xenograft model of H929 MM cells. This can be correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels. [1] AS703026 (10 mg/kg) inhibits tumor growth, and markedly decreases p-ERK level in a xenograft mouse model of human K-Ras mutated (D-MUT) colorectal tumor. [2]
動物実験 動物モデル H929 MM xenografts are established in CB17 (SCID) mice
投与量 15 or 30 mg/kg
投与経路 Oral gavage twice daily
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01985191 Completed
Neoplasm Malignant
Sanofi|Merck KGaA Darmstadt Germany
November 2013 Phase 1
NCT01713036 Completed
Locally Advanced or Metastatic Solid Tumors
Merck KGaA Darmstadt Germany
November 30 2012 Phase 1
NCT01668017 Terminated
Advanced Solid Tumors|Hepatocellular Carcinoma
Merck KGaA Darmstadt Germany|Merck Serono Co. Ltd. Japan
September 30 2012 Phase 1
NCT01378377 Terminated
Advanced Solid Tumor
EMD Serono
May 27 2011 Phase 1

化学情報

分子量 431.20 化学式

C15H15FIN3O3

CAS No. 1236699-92-5 SDF Download Pimasertib (AS-703026) SDFをダウンロードする
Smiles C1=CC(=C(C=C1I)F)NC2=C(C=CN=C2)C(=O)NCC(CO)O
保管

In vitro
Batch:

DMSO : 86 mg/mL ( (199.44 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。

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