PD0325901

PD0325901は選択的です、そして、非ATP競争的有糸分裂促進物質はMEK活動のinhibitonのためにプロテインキナーゼ・キナーゼ(MEKまたはMAPKK)MEK阻害剤を起動させました。IC50 が 0.33 nMになる。

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PD0325901 化学構造
分子量: 482.19

品質と確認

製品表彰状(69)

カスタマーレビュー(10)

Quality Control & MSDS

製品情報

  • Compare MEK Inhibitors
    MEK阻害剤を比較
  • 研究分野
  • Combination Therapy
    併用療法

製品の説明

生物活性

情報 PD0325901は選択的です、そして、非ATP競争的有糸分裂促進物質はMEK活動のinhibitonのためにプロテインキナーゼ・キナーゼ(MEKまたはMAPKK)MEK阻害剤を起動させました。IC50 が 0.33 nMになる。
目標

MEK

IC50

0.33 nM [1]

In vitro試験 PF0325901 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 Kiapp 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]
In vivo試験 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]
臨床試験 Combined with PF-04691502/PF-05212384/CPT-11, PD-0325901 is currently in Phase I clinical trial for advanced cancer.
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ:

[1]

In vitro cascade 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.

細胞アッセイ:

[3]

細胞系 PTC cells
濃度 0.1 nM- 1 μM
処理時間 48 hours
方法

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.

動物実験:

[3]

動物モデル Ncr-nu/nu mice bearing PTC cells
製剤 80 mM citric buffer (pH 7)
投薬量 20-25 mg/kg
管理 Oral gavage
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol 8 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download PD0325901 SDF
分子量 482.19
化学式

C16H14F3IN2O4

CAS No. 391210-10-9
保管 2年-20℃
6月-80℃in DMSO
別名
溶解度 (25°C) * In vitro DMSO 96 mg/mL (199 mM)
<1 mg/mL (<1 mM)
エタノール 40 mg/mL (82 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 8 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide

研究分野

カスタマーレビュー (10)


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Rating
Source Cancer Res, 2009, PD0325901 purchased from Selleck
Method
Cell Lines
Concentrations 10 mg/kg
Incubation Time
Results "In all three tissues, the PD325901 compound blocks phosphorylation of ERK similarly. In contrast, RDEA119 exhibits tissue selectivity, showing little or no inhibition in brain, significantly lower effect in lung, and sustained efficacy in tumor tissue. The levels of RDEA119 in the lung are similar to the concentration in plasma, whereas the levels in the brain are much lower than in the plasma, suggesting that RDEA119 has low central nervous system (CNS) penetration. In contrast, concentrations of PD325901 are higher in the brain than in plasma.

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Rating
Source J Bone Miner Res, 2011, 26, 2486-2497. PD0325901 purchased from Selleck
Method qPCR analysis, Western blot
Cell Lines UMR-106 cells
Concentrations 100 nM
Incubation Time 3/24 h
Results To test for the dependence of MAPK signaling in the transcriptional regulation of Fgf23, we treated UMR-106 cells with the MEK inhibitor PD0325901 and the RAF inhibitor RAF265(Fig.B and D). We found that inhibition of MEK or RAF alone was not sufficient to fully block FGF9-mediated phosphorylation of ERK1/2 and the induction of Fgf23.

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Source Breast Cancer Res, 2011, 13, R36. PD0325901 purchased from Selleck
Method Assessment of MEK inhibitor toxicity
Cell Lines MDA-MB-453 xenograft model
Concentrations 5/10/15/20 mg/kg/day
Incubation Time 30 days
Results We observed a significantly higher weight gain in mice treated with PD0325901 at 5 a nd 10 mg/kg/day doses compared to the control group( P <0.01, Figure A). Importantly, treatments with higher doses of PD0325901 at 15 and 20 mg/kg/day resulted in a significant weight reduction compared to the lower doses of this agent (P <0.01, Figure A). Furthermore, the number of treatment days lost due to toxicity was significantly lower with PD0325901 doses of 5 and 10 mg/kg/day compared to that of 15 and 20 mg/kg/day( P< 0.01, Figure 5B ). Notably, PD0325901 treatment at 5mg/kg/day did not result in any measurable toxicity using this approach (FigureA and B) . These findings indicate that PD0325901 treatment at lower doses is significantly less toxic than higher doses of this agent in a xenograft mouse model.

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Source Breast Cancer Res, 2011, 13, R36. PD0325901 purchased from Selleck
Method Immunohistochemistry
Cell Lines xenograft tumor
Concentrations
Incubation Time
Results Angiogenesis was significantly lower in the combination therapy group with a CD31-positive blood vessel count of 5.3 ± 3 compared to that of control (44± 6) and monotherapy groups (flutamide: 43 ± 7, PD0325901: 24 ± 7) (P < 0.03, Figure A to D ) . Moreover, CD-31- positive blood vessels in the combination therapy group were smaller and less distinct than those in other groups (Figure B to D).

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Source Stem Cells Dev, 2013, PD0325901 purchased from Selleck
Method Colony forming assay
Cell Lines iPS cells
Concentrations 2 uM
Incubation Time 18 day
Results To see if the addition of other small molecule inhibitors improves the efficacy of iPSC induction from myoblast cells in feeder-free conditions, ALK4/5/7 inhibitor SB431542 (SB), MEK inhibitor PD0325901 (PD), nonspecific GSK3 inhibitor lithium chloride (LiCl), and HDAC inhibitor VPA, all reported to enhance the efficiency of iPSC inductions, were tested in combination with NaB (Fig. 2C, D, and Supplementary Fig. S2). Addition of SB to the NaBcontaining medium enhanced the induction efficiency compared with NaB only. Further addition of PD or LiCl to the mixture did not further improve the efficiency.

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Rating
Source J Genet Genomics, 2012, 39, 643e651. PD0325901 purchased from Selleck
Method Rat embryoid bodies (rEBs) formation
Cell Lines rES cells
Concentrations 0.75 uM
Incubation Time 4 d
Results For the first 2 days of rEBs formation, rES cells were cultured in CM in the presence of Rho kinase inhibitor, Y-27632 (10 umol/L) and 2i (PD0325901, 0.1 umol/L; CHIR99021, 0.75 umol/L; Selleck, USA). Thereafter, we transferred the regular rEBs into CM supplemented with 2i and without Y-27632 for another 2 days. On day 4, abundant highquality rEBs formed and then 2i was eliminated from the media.

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Rating
Source Int J Proteomics, 2011, 2011, Article ID 215496. PD0325901 purchased from Selleck
Method Nikon inverted-phase microscope
Cell Lines lung tumor cell lines
Concentrations 0.1/1 µM
Incubation Time Two weeks
Results Proliferation of cell colony size in the H1734 cells was potently blocked by treatment with the downstream MEK inhibitor PD-325901 as seen when these cells were grown in cell culture.

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Rating
Source Dr. Citrin, Deborah of NIH. PD0325901 purchased from Selleck
Method Western blot
Cell Lines HT29 Xenograft tumors
Concentrations 1 mg/kg
Incubation Time 24 h
Results Effects of PD0325901 on HT29 Xenograft tumors. PD0325901(1mg/kg carrier DMSO).Collection at 24h.

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Rating
Source , , Bone. 2014 Feb;59:151-61. PD0325901 purchased from Selleck
Method histological analysis
Cell Lines MEKi treated mice
Concentrations 10 mg/kg
Incubation Time 10-21 days
Results Mice treated with MEKi after the establishment of the cartilaginous soft callus (Late group, days 10-21) showed an increase in the amount of cartilage remaining. This cartilage appeared characteristically hypertrophic and mineralized.

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Rating
Source PD0325901 purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-10 nM
Incubation Time 24 h
Results

製品表彰状 (69)

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