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

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Quality Control & MSDS

製品説明

  • Compare MEK Inhibitors
    MEK製品生物活性の比較
  • 研究分野
  • Combination Therapy
    併用療法

製品の説明

生物活性

製品説明 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。
ターゲット

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

プロトコル (参考用のみ)

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.

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
投与方法 Oral gavage

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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 solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 96 mg/mL (199.09 mM)
エタノール 40 mg/mL (82.95 mM)
<1 mg/mL (<1 mM)
In vivo 30% PEG 400+5% Tween 80+ddH2O 10mg/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

文献中の引用 (86)

Frequently Asked Questions

  • Question 1
    Whether the inhibitor PD0325901 interacts with other targets other than MEK?

    Answer: 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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