Mirdametinib (PD0325901)

製品コード：S1036 純度：99.99%

ミルダメチニブ (Mirdametinib (PD0325901)) は選択的非 ATP 競合性 MEK 阻害剤です。Cell-free assay における IC50 は0.33 nM で、ERK1 および ERK2 のリン酸化に対して CI-1040 よりも約 500 倍の活性を有しています。臨床第2相試験中

CAS No. 391210-10-9

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
25mg	JPY 56500	国内在庫あり
100mg	JPY 115500	国内在庫あり
1g	JPY 295500	国内在庫あり

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現在のバッチを見る：純度： 99.99%

99.99

Mirdametinib (PD0325901)と併用されることが多い化合物

SB431542

Mirdametinib and SB431542 combination synergizes tumor cell proliferation inhibition in HeLa (CBP60232)/SCC‑15 (CBP61034)/5637 (CBP60309) cell lines.

Zhang Y, et al. Oncol Rep. 2019;41(6):3545-3554.

Laduviglusib (CHIR-99021)

PD0325901 and CHIR99021 can induce the reprogramming of Mouse Fibroblasts (MEF) into Small Molecule-Induced Neural Stem (SMINS) Cells.

Han YC, et al. Stem Cells Int. 2016;2016:4304916.

SB590885

Mirdametinib and SB590885, along with other small-molecule inhibitors, perform critical roles in the transdifferentiation of naive human pluripotent stem cells (hPSC) to trophoblast stem cells (TSC).

Roberts RM, et al. Cell Mol Life Sci. 2022 Jul 25;79(8):447.

WH-4-023

Mirdametinib and WH-4-023, along with other small-molecule inhibitors, perform critical roles in the transdifferentiation of naive human pluripotent stem cells (hPSC) to trophoblast stem cells (TSC).

Roberts RM, et al. Cell Mol Life Sci. 2022 Jul 25;79(8):447.

Mirdametinib (PD0325901)関連製品

関連ターゲット	MEK1 MEK1/2 MEK2 MEK5	もっと見る
関連製品	U0126-EtOH PD98059 PD184352 (CI-1040) BIX 02189 Pimasertib (AS-703026) Refametinib (RDEA119) TAK-733 AZD8330 BIX 02188 GDC-0623 SL-327 Myricetin BI-847325 PD318088 APS-2-79 HCl	もっと見る
関連化合物ライブラリー	Kinase Inhibitor Library MAPK Inhibitor Library Cell Cycle compound library TGF-beta/Smad compound library Anti-alzheimer Disease Compound Library	もっと見る

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

阻害剤	Citation	MEK	MEK1	MEK1/2	MEK2	MEK5	その他
Mirdametinib (PD0325901)	802	++++
U0126-EtOH	770		++		++
PD184352 (CI-1040)	138		+++		+++
PD98059	504		+				AhR
BIX 02189	73					++++	ERK5
Pimasertib (AS-703026)	44			+
Pelitinib (EKB-569)	11	+					EGFR,Src,ErbB2
BIX 02188	11					+++
TAK-733	24		++++
AZD8330	18			+++			ERK phosphorylation
SL-327	12		+		+		AP-1
Refametinib (RDEA119)	27		++		++
Nedometinib	0		+				p-ERK
RGB-286638 free base	0		++				cyclin T1-CDK9,cyclin B1-CDK1,GSK-3β
Zapnometinib (PD0184264)	0	+++
RO4987655	0	+++
GDC-0623	13		++++
BI-847325	7		++		+++		Aurora B (Xenopus laevis),Aurora C (Human),Aurora A (Human)
Avutometinib	20		+				BRAF V600E,BRAF,CRAF
PD318088	6			✔
Honokiol	33	✔					Akt-phosphorylation
NST-628	0	✔					Raf
PD184161	0	✔
GW284543 (UNC10225170)	0					✔
APS-2-79 HCl	2	✔					KSR2
Myricetin	8		✔				PI3Kγ

1. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation. 2. "✔" indicates inhibitory effect, but without specific value.

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	活性情報	PMID
rhabdomyosarcoma	Inhibition of MEK1 phosphorylation in human	0.4 to 10 uM	1 hr	Inhibition of MEK1 phosphorylation in human rhabdomyosarcoma cells infected with EV71 BC08 GU475127 assessed as inhibition of ERK1/2 phosphorylation at 0.4 to 10 uM pre-treated for 1 hr followed by viral infection measured after 24 hrs by western blotting	27288186
rhabdomyosarcoma	Induction of MEK1/2 phosphorylation in human	0.4 to 10 uM	1 hr	Induction of MEK1/2 phosphorylation in human rhabdomyosarcoma cells infected with EV71 BC08 GU475127 at 0.4 to 10 uM pre-treated for 1 hr followed by viral infection measured after 24 hrs by western blotting analysis	27288186
PANC1	Inhibition of MEK1 in human	10 uM	1 hr	Inhibition of MEK1 in human PANC1 cells assessed as reduction in pErk1/2 level at 10 uM after 1 hr by Western blotting analysis	25766633
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生物活性

製品説明

Targets

MEK ^[1]
(Cell-free assay)

0.33 nM

In Vitro
In vitro	PD0325901 shows higher permeability than CI-1040, another MEK inhibitor. PD0325901 should be able to achieve higher systemic exposures than CI-1040. ^[1] PD0325901 is exquisitely specific and highly potent against purified MEK, revealing a K_i^app of 1 nM against activated MEK1 and MEK2. ^[2] PD0325901 is roughly 500-fold more potent than CI-1040 with respect to its cellular effects on phosphorylation of ERK1 and ERK2, displaying subnanomolar activity. ^[2] PD0325901 prevents the growth of melanoma cell lines. PD0325901 inhibits the growth of TPC-1 cells and K2 cells with GI50 of 11 nM and 6.3 nM, respectively. ^[3] PD0325901 significantly prevents the the growth of PTC cells harboring a BRAF mutation at very low concentration (10 nM) and only moderately increases the growth of the PTC cells carrying the RET/PTC1 rearrangement at the same concentration. PD0325901 effectively inhibits the phosphorylation of ERK1/2 in multiple PTC cell lines. ^[3]
Kinase Assay	In vitro cascade assay
Kinase Assay	Incorporation of ³²P into myelin basic protein (MBP) is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) and a glutathione S-transferase protein containing p45MEK (GST-MEK). The assay solution contained 20 mM HEPES, pH 7.4, 10 mM MgCl₂, 1 mM MnCl₂, 1 mM EGTA, 50 mM [gamma-³²P]ATP, 10 mg GST-MEK, 0.5 mg GST-MAPK and 40 mg MBP in a final volume of 100 mL. Reactions are stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C filter mat. ³²P retained on the filter mat is determined using a 1205 Betaplate. PD0325901 is assessed at various dose ranges in order to determine dose response curves.
細胞実験	細胞株	PTC cells
	濃度	0.1 nM- 1 μM
	反応時間	48 hours
	実験の流れ	PTC cells (1 × 10⁴) are seeded in 24-well plates with 1 mL of medium for 4 days in a 37 °C incubator. MEK inhibitor PD0325901 at varying concentrations is added to the cells in triplicate on day 0. MTT dissolved in 0.8% NaCl solution at 5 mg/mL is added to each well (0.2 mL) on day 2 to test GI50 or every day for cell growth curves. The cells are incubated at 37 °C for 3 hours with MTT. The liquid is then aspirated from the wells and discarded. Stained cells are dissolved in 0.5 mL of DMSO and their absorption at 570 nm is measured using a Synergy HT multidetection microplate reader. For GI50, cell growth is calculated as 100 × (T − T₀)/(C − T₀), where T is the optical density of the wells treated with inhibitors after a 48-hour period, T₀ is the optical density at time zero, and C is the control optical density with DMSO only.
実験結果図	Methods	Biomarkers	結果図	PMID
	Western blot	p-ERK / p-AKT / Cyclin D1 / p27 p-p70S6K(T389) / p4EBP1(S65) / pS6(S235) cleaved PARP DR5		22573716
	Immunofluorescence	Fibronectin / Actin / pFAK ZO-1		28187762

In Vivo
In Vivo	The improved potency of PD0325901 relative to CI-1040 is evident. A single oral dose of PD0325901 (25 mg/kg) inhibits phosphorylation of ERK by more than 50% at 24 hours post-dosing. In contrast, CI-1040 at a much higher dose (150 mg/kg) only inhibit pERK levels for roughly 8 hours, returning to control levels by 24 hours after treatment. ^[2] Therefore, the dose required to produce a 70% incidence of complete tumor responses (C26 model) is 25 mg/kg/day versus 900 mg/kg/day for PD0325901 and CI-1040, respectively. Anticancer activity of PD 0325901 has been demonstrated for a broad spectrum of human tumor xenografts. ^[2] After 1 week of oral administration of PD0325901 (20–25 mg/kg/day) in mice, no tumor growth is detected in mice inoculated with PTC cells bearing a BRAF mutation. ^[3] For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor is decreased by 58% as compared with controls. In conclusion, PTC cells carrying a BRAF mutation are more sensitive to PD0325901 than are PTC cells carrying the RET/PTC1 rearrangement. ^[3]
動物実験	動物モデル	Ncr-nu/nu mice bearing PTC cells
	投与量	20-25 mg/kg
	投与経路	Oral gavage

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT02510001	Completed	Solid Tumor\|Colorectal Cancer	University of Oxford\|Queen''s University Belfast\|Oxford University Hospitals NHS Trust\|Velindre NHS Trust\|University Hospital Antwerp\|Hospital Vall d''Hebron\|Saint Antoine University Hospital\|European Georges Pompidou Hospital\|Pfizer\|University of Turin Italy\|Belfast Health and Social Care Trust\|Beaumont Hospital\|European Commission\|Array BioPharma\|University of Paris 5 - Rene Descartes	November 2014	Phase 1
NCT02096471	Completed	Neurofibromatosis Type 1 and Growing or Symptomatic Inoperable PN	University of Alabama at Birmingham	June 2014	Phase 2
NCT02022982	Completed	KRAS Mutant Non-Small Cell Lung Cancer\|Solid Tumors	Dana-Farber Cancer Institute	January 2014	Phase 1
NCT01347866	Terminated	Advanced Cancer	Pfizer	October 2011	Phase 1
NCT00174369	Terminated	Carcinoma Non-Small-Cell Lung	Pfizer	November 2005	Phase 2

参考
[1] Barrett SD, et al. Bioorg Med Chem Lett, 2008, 18(24), 6501-6504. [2] Judith SS, et al. Proc Amer Assoc Cancer Res.2004,45, Abstract #4003 [3] Henderson YC, et al. Mol Cancer Ther, 2010, 9(7), 1968-1976. [4] Paterson A, et al. Blood, 2012, 119(7), 1726-1736. [5] Ricciardi MR, et al. J Mol Med (Berl), 2012, 90(10), 1133-1144. [6] Pratilas CA, et al. Cancer Res, 2008, 68(22), 9375-9383. [7] Legrier ME, et al. Cancer Res, 2007, 67(23), 11300-11308. [8] Barrett SD, et al. Bioorg Med Chem Lett, 2008, 18(24), 6501-6504. + 展開

参考

+ 展開

化学情報

分子量	482.19	化学式	C₁₆H₁₄F₃IN₂O₄
CAS No.	391210-10-9	SDF	Download Mirdametinib (PD0325901) SDFをダウンロードする
Smiles	C1=CC(=C(C=C1I)F)NC2=C(C=CC(=C2F)F)C(=O)NOCC(CO)O
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 ( (199.09 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 : 96 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

5%DMSO 1 40%PEG300 Click to order 2 5%Tween 80 Click to order 3 50%ddH2O

5.0mg/ml (10.37mM)

Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

Clear solution

5% DMSO 1 95% Corn oil

0.4mg/ml (0.83mM)

Taking the 1 mL working solution as an example, add 50 μL of 8 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. 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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よくある質問（FAQ）

質問1:
Whether the inhibitor PD0325901 interacts with other targets other than MEK?

回答
PD0325901 has very high selectivity to MEK. In addition, it can also inhibits VEGF activity according to the reference: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713590/

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