PD184352 (CI-1040)

製品コード：S1020 純度：99.96%

PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM in cell-based assays, 100-fold more selective for MEK1/2 than MEK5. PD184352 (CI-1040) selectively induces apoptosis.

CAS No. 212631-79-3

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 29500	国内在庫あり
5mg	JPY 22000	国内在庫あり
10mg	JPY 34000	国内在庫あり
25mg	JPY 55500	国内在庫あり
100mg	JPY 100500	国内在庫あり
1g	JPY 295500	国内在庫なし(納期7~10日)

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PD184352 (CI-1040)関連製品

関連ターゲット	MEK1 MEK1/2 MEK2 MEK5	もっと見る
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シグナル伝達経路

MEK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	活性情報	PMID
U937	Cytotoxicity assay	30 uM	Cytotoxicity against human U937 cells assessed as inhibition of [3H]thymidine incorporation at 30 uM by MTS assay	20580230
U937	Function assay	3 uM	Inhibition of ERK phosphorylation in human U937 cells at 3 uM by Western blotting	20580230
U937	Function assay	3 uM	Inhibition of RSK1 phosphorylation in human U937 cells at 3 uM by Western blotting	20580230
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生物活性

製品説明

特性

First MEK inhibitor to begin clinical development.

Targets

MEK1 ^[1] (Cell-free assay)	MEK2 ^[1] (Cell-free assay)
17 nM	17 nM

In Vitro
In vitro	CI-1040 treatment produces a reduction of pMAPK levels in multiple tumor cells including Colon 26, BX-PC3 pancreatic, A431 cervical, HT-29 colon, ZR-25-1 breast and SKOV-3 ovarian carcinomas. CI-1040 treatment doesn't inhibit the phosphorylation of Jun kinase, p38 kinase or Akt, indicating CI-1040 specifically targets MEK. Inhibition of MAPK activation by CI-1040 prevents cell cycle progression and induces a G1 block. ^[1] The IC50 for inhibition of MEK1 by CI-1040 is 0.3 μM, 15-fold higher than the concentration required to inhibit the EGF-induced activation of ERK2 in Swiss 3T3 cells. These results indicate CI-1040 exerts its effects on cells by suppressing the activation of MKK1, and not by blocking its activity. 2 nM PD184352 inhibits the activation of MKK1 in Swiss 3T3 cells by 50%, while over 100-fold concentration of CI-1040 inhibits MEK1 in vitro. PD184352 also inhibits the Raf-catalysed phosphorylation of MEK1 without any effect on the Raf-catalysed phosphorylation of myelin basic protein. ^[2] CI-1040 inhibits 86% of papillary thyroid carcinoma (PTC) cell growth with the RET/PTC1 rearrangement at 10μM compared with cells treated with DMSO only. CI-1040 shows potent inhibition to PTC cells (BRAF mutation) with GI50 of 52 nM, but low activity to RET/PTC1 rearrangement type with GI50 of 1.1 μM. ^[3] A recent research indicates CI-1040 increases the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. ^[4]
Kinase Assay	MEK1 Assay
Kinase Assay	MAP kinase is activated after phosphorylation by MEK; the activated MAP kinase subsequently phosphorylates myelin basic protein (MBP).Incorporation of ³²P into myelin basic protein (MBP) is assayed in the presence of glutathione S-transferase (GST) fusion proteins containing the 44-kDa MAPK (GST-MAPK) or the 45-kDa MEK (GST-MEK1). Assays are conducted in 50μL of 50 mM Tris, pH 7.4/10 mM MgCl₂ /2 mM EGTA/10 μM [γ-³²P]ATP containing 10 μg of GST-MEK1, 0.5 μg of GST-MAPK, and 40 μg of MBP. After incubation at 30°C for 15 minutes, reactions are stopped by addition of Laemmli SDS sample buffer. Phosphorylated MBP is resolved by SDS/10% PAGE. This screening effort leads to the discovery of several small-molecule inhibitors of MEK, i.e. CI-1040. Experiments assessing the order of addition shows that CI-1040 directly inhibits MEK1 with a 50% inhibitory concentration (IC50) of 17 nM, without affecting the activity of MAPK.
細胞実験	細胞株	Colon 26 carcinoma cells
	濃度	0.1-10 μM
	反応時間	24 hours
	実験の流れ	Cells are planted seeded in T-75 cm ² flasks and treated the next day for 24 hous with either DMSO or CI-1040. Single-cell suspensions are collected, and pellets are fixed in ice-cold ethanol (70%) for 30 minutes. After centrifugation of the samples, propidium iodide (50 μg/mL) and RNase (30 units/mL) are added to the pellets for 20 minutes at 37 °C. After filtration, samples are analyzed by flow cytometry.
実験結果図	Methods	Biomarkers	結果図	PMID
	Western blot	p-ERK1/2 / ERK1/2 p-ERK5 / ERK5		21762482
	Growth inhibition assay	Cell viability		29989268

In Vivo
In Vivo	Oral dosing of CI-1040 impairs the growth of colon tumor xenografts of mouse and human with a wide dose range of 48-200 mg/kg per dose, but not of P388 leukemia. ^[1] CI-1040 inhibits the tumor xenografts from PTC cells carrying a BRAF mutation with 31.3% reduction, carrying the RET/PTC1 rearrangement with 47.5% reduction than in untreated (vehicle) mice after 3 weeks of oral administration (300 mg/kg/d). No toxic effects are observed in any mice when they are treated with CI-1040. ^[2] Transient exposure of mammary tumors to CI-1040 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth. Combined treatment with CI-1040 (25 mg/kg) and UCN-01 (0.1-0.2 mg/kg) significantly reduces MDA-MB-231, and largely abolishs MCF7 tumor growth in implanted athymic mice, while either single treatment has no significant activity. The drug combination leads to profound tumor cell death which correlates with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. ^[5]
動物実験	動物モデル	PTC cells in athymic mice
	投与量	150 mg/kg
	投与経路	Orally twice daily

参考
[1] Sebolt-Leopold JS, et al. Nat Med, 1999, 5(7), 810-816. [2] Davies SP, et al. Biochem J, 2000, 135(1), 95-105. [3] Henderson YC, et al. Arch Otolaryngol Head Neck Surg, 2009, 135(4), 347-354 [4] Pellicano F, et al. Leukemia, 2011, 25(7), 1159-1167. [5] Hawkins W, et al. Cancer Biol Ther, 2005, 4(11), 1275-1284. [6] Legrier ME, et al, Cancer Res, 2007, 67(23), 11300-11308. [7] Ou DL, et al, Clin Cancer Res, 2009, 15(18), 5820-5828. [8] Jimeno A, et al, Mol Cancer Ther, 2007, 6(3), 1079-1088. + 展開

参考

+ 展開

化学情報

分子量	478.67	化学式	C₁₇H₁₄ClF₂IN₂O₂
CAS No.	212631-79-3	SDF	Download PD184352 (CI-1040) SDFをダウンロードする
Smiles	C1CC1CONC(=O)C2=C(C(=C(C=C2)F)F)NC3=C(C=C(C=C3)I)Cl
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1年-80°Cin solvent
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	１ケ月-20°Cin solvent

In vitro
Batch:

DMSO : 96 mg/mL ( (200.55 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 : 14 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

Clear solution

30%PEG400 Click to order 1 0.5%Tween 80 Click to order 2 5%propylene glycol, pH 9

10.0mg/ml (20.89mM)

Taking the 1 mL working solution as an example, add 300 μL of 33.33 mg/ml clarified PEG400 stock solution to 5 μL of Tween80, mix evenly to clarify it; add 50 μL Propylene glycol, pH 9, to the above system, mix evenly to clarify it; then continue Add 645 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

実験計算

モル濃度計算器

質量	濃度	体積	分子量
=	×	×

希釈計算器分子量計算器

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）

投与量 mg/kg 動物平均体重 g 投与体積（動物毎）μL 動物数匹

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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