BIX 02189 化学構造
分子量: 440.54

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Quality Control & MSDS

製品説明

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製品の説明

生物活性

製品説明 BIX 02189は、1.5nMのIC50によるMEK5の選択的な阻害剤です。
ターゲット

MEK5

IC50

1.5 nM [1]

In vitro試験 BIX02189 blocks MEK5 and ERK5 catalytic activity with IC50 values of 1.5 nM and 59 nM, respectively. They are more potent than the effect caused by BIX02188 with IC50 values of 4.3 nM and 810 nM, respectively. BIX02189 shows inhibitory activity against CSF1R (FMS) with IC50 of 46 nM but displays no activity against related kinases MEK1, MEK2, ERK1, p38α, JNK2, EGFR, and STK16 with IC50 values of >3.7 μM. Pretreatment with BIX02189 inhibits sorbitol-induced phosphorylation of ERK5 in HeLa cells in a dose dependent manner, and displays no inhibitory activity against the phosphorylation of ERK1/2, p38, and JNK1/2 MAPKs. Treatment with only BIX02189 for 24 hours in HeLa or HEK293 cells does not show any cytotoxic effect. BIX02189 inhibits MEK5/ERK5/MEF2C-driven luciferase expression in HeLa and HEK293 cells with IC50 values of 0.53 μM and 0.26 μM, respectively. This is a more significant than the effect caused by BIX02188. [1] BIX02189 inhibits the activation of ERK5, and suppresses C-terminus of Hsc70-interacting protein (CHIP) mediated p53 ubiquitination, leading to the reverse of the protective effect caused by laminar flow (L-flow) in human umbilical vein endothelial cells (HUVECs) exposed to 15d-PGJ2. [2] BIX02189 (10 uM) inhibits ERK5 phosphorylation, and reduces myocyte enhancer factor 2 (MEF2) transcriptional activity in neonatal rat cardiomyocytes (NRCMs) stimulated by isoproterenol. BIX02189 enhances the sorbitol induced apoptosis in NRCMs, confirming the protective role of ERK5 in cardiomyocytes. [3]
In vivo試験
臨床試験
特集

プロトコル (参考用のみ)

キナーゼアッセイ:

[1]

Catalytic assay MEK5 protein isolated from the baculovirus expression system is used to measure kinase activity utilizing PKLight ATP Detection Reagent. The assay is performed using 15 nM GST-MEK5 and 0.75 μM ATP in assay buffer consisting of 25 mM Hepes, pH 7.5, 10 mM MgCl2, 50 mM KCl, 0.2% BSA, 0.01% CHAPS, 100 μM Na3VO4, 0.5 mM DTT and 1% DMSO in the presence of varying concentrations of BIX02189. The kinase reaction mixture is incubated for 90 minutes at room temperature followed by addition of 10 μL of ATP detection reagent for 15 minutes. The relative light unit (RLU) signal is measured and the RLU signals are converted to percent of control (POC) values for the determination of IC50 value.

細胞アッセイ:

[1]

細胞株 HeLa cells
濃度 Dissolved in DMSO, final concentration ~10 μM
反応時間 Pretreatment for 1.5 hours
実験の流れ

The cells are serum starved for 20 hours prior to stimulation with sorbitol at a final concentration of 0.4 M for 20 minutes at 37 °C. BIX02189 is added 1.5 hours prior to the addition of sorbitol. The cells are harvested and lysed in 50 μL RIPA buffer containing Halt protease and phosphate inhibitors at 4 °C for 5-10 minutes. The lysates are centrifuged for 10 minutes at 14,000 rpm and 50 μL lysate is added to 50 μl 2× sample buffer and boiled for 4 minutes at 95 °C. Twenty microliters sample is run on SDS–PAGE 10% Tris-glycine gels and transferred to nitrocellulose. Western blotting is done with appropriate antibodies.

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 BIX 02189 SDF
分子量 440.54
化学式

C27H28N4O2

CAS No. 1094614-85-3
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 60 mg/mL warmed (136.19 mM)
エタノール 80 mg/mL (181.59 mM)
<1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 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 (Z)-3-((3-((dimethylamino)methyl)phenylamino)(phenyl)methylene)-N,N-dimethyl-2-oxoindoline-6-carboxamide

カスタマーフィードバック (7)


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Rating
Source J Biol Chem, 2012, 287, 40722-31. BIX 02189 purchased from Selleck
Method Western Blot
Cell Lines HUVEC
Concentrations 10uM
Incubation Time 16-24h
Results A biochemicalexperiment showed that flow-induced Nrf2 nuclear translocationwas diminished by inhibiting ERK5 with BIX02189 (Fig. 4A), indicating that the kinase activity of ERK5 may be involvedin ERK5-induced Nrf2 transcriptional activation and nucleartranslocation.

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Rating
Source J Biol Chem, 2012, 287, 40722-31. BIX 02189 purchased from Selleck
Method Mice and en Face Experiments
Cell Lines 6-week-old male C57BL/6 mice
Concentrations 10 mg/kg
Incubation Time
Results Flow-dependent nuclear localization of Nrf2 was inhibited by BIX02189, aspecific inhibitor of MEK5, in aorta of mice in vivo.

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Rating
Source J Biol Chem, 2012, 287, 40722-31. BIX 02189 purchased from Selleck
Method Western Blot
Cell Lines HUVEC
Concentrations 10uM
Incubation Time 16-24h
Results Flow-induced expression of HO-1, NQO1, and eNOS was also inhibited by pretreatment of BIX02189 (Fig. B).

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Rating
Source Biochem Biophys Res Commun, 2012, 421, 490–493. BIX 02189 purchased from Selleck
Method Western Blot, ELISA
Cell Lines HK-2 cells
Concentrations 10-20uM
Incubation Time 17 h
Results PARP cleavage was further enhanced bytreatment with BIX02189 (20 lM) in cells exposed to 20 lM butnot 50 lM CdCl2 (Fig. 4A, lanes 5 and 6). Consistent with thesefindings, BIX02189 (20 uM) increased the level of cytoplasmicnucleosomes in HK-2 cells treated with 20 lM CdCl2 for 16 h(Fig. 4B).

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Rating
Source Biochem Biophys Res Commun, 2012, 421, 490–493. BIX 02189 purchased from Selleck
Method Western Blot
Cell Lines HK-2 cells
Concentrations 5-50uM
Incubation Time 3-5 h
Results treatment of HK-2 cells with 5–50 μM BIX02189suppressed CdCl2 (50 μM)-induced ERK5 phosphorylation in adose-dependent manner, whereas the level of total ERK5 was unchanged in this range (Fig. 3). On the other hand, CdCl2-inducedphosphorylation of ERK1/2 was not affected by BIX02189. At 4 h,CdCl2 (50 μM)-induced accumulation of phosphorylated CREB andATF-1, and accumulation of mobility-shifted c-Fos protein weresuppressed by treatment with BIX02189 at 10 or 20 μM.BIX02189 treatment did not affect the level of total ERK1/2, totalCREB, or actin.

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Rating
Source J IMMUNOTOXICOL, 2013, 10, 32-39. BIX 02189 purchased from Selleck
Method Western Blot
Cell Lines neutrophils (PMN) cells
Concentrations 30 uM
Incubation Time 1 h
Results After applying the ERK5 pathway inhibitor (BIX02189)no changes of iNOS expression in the cytoplasmicFraction of PMN exposed to NDMA were shown, ascompared to cells incubated without the inhibitor. Anincreased Fra-1 and JunB expression was observed inboth fractions of analyzed cells, as compared to cellsincubated without the inhibitor. After inhibiting the ERK5pathway no changes in Fra-2 and FosB expression in thecytoplasmic fraction were observed. An increased Fra-2expression and reduced FosB expression were shown inthe nuclear fraction. No changes in JunD expression inboth PMN fractions were observed.

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Rating
Source Dr. Franco Izzo of Institute of Biology and Experimental Medicine. BIX 02189 purchased from Selleck
Method Western blot
Cell Lines T47D cells
Concentrations 0/10/20/30/50 μM
Incubation Time 45 min
Results BIX 02189 treatment resulted in a reduction of ERK5 phosphorylation in T47D cells.

文献中の引用 (22)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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