BIRB 796 (Doramapimod) 化学構造
分子量: 527.66

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Quality Control & MSDS

製品説明

  • Compare p38 MAPK Inhibitors
    p38 MAPK製品生物活性の比較
  • 研究分野
  • BIRB 796 (Doramapimod)のメカニズム

製品の説明

生物活性

製品説明 BIRB 796 (Doramapimod)はp38αMAPKの高さ選択阻害剤、THP-1細胞に作用する時、EC50が18nMになる。
ターゲット

p38α MAPK

IC50

0.1 nM (Kd) [1]

In vitro試験 BIRB 796 shows no significant inhibition to ERK-1, SYK, IKK2β, ZAP-70, EGF receptor kinase, HER2, protein kinase A (PKA), PKC, PKC-α, PKC-β (I and II) and PKC-γ. BIRB 796 greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38α. BIRB 796 represents one of the most potent and slowest dissociating inhibitors against human p38 MAP kinase now known. [1] BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC50 of 1.4 and 0.1 nM, respectively. [2] BIRB796 also inhibits the activity and the activation of SAPK3/p38γ at a higher concentration than it does in p38α. BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38γ. BIRB796 blocks JNK1/2 activation and activity in HEK293 cells, while not inhibits the activation and activity of ERK1/ERK2 in Hela cells. Moreover, the binding of BIRB796 to the p38 MAPKs or JNK1/2 is impairing their phosphorylation by the upstream kinase MKK6 or MKK4 rather than enhancing their dephosphorylation. [3] BIRB 796 blocks baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. BIRB 796 downregulates IL-6 and VEGF secretion in BMSCs triggered by TNF-α and TGF-β1. [4] BIRB-796 has a pyrazole scaffold that places a lipophilic t-butyl group into the lower selectivity site and a tolyl ring into the upper selectivity site. BIRB-796 also inhibits B-Raf and Abl with IC50 of 83 nM and 14.6 μM, respectively. [5]
In vivo試験 BIRB 796 (30 mg/kg) inhibits 84% of TNF-α in LPS-stimulated mice and demonstrates efficacy in a mouse model of established collagen-induced arthritis. [1] BIRB 796 has good pharmacokinetic performance even after oral administration in mice. [2]
臨床試験 Boehringer Ingelheim has announced the discontinuation of BIRB 796 R&D project in 2005.
特集 The first p38 MAPK inhibitor to be tested in a phase III clinical trial.

プロトコル (参考用のみ)

キナーゼアッセイ:

[6]

Procedures for the THP-1 cellular assay for inhibition of LPS-stimulated TNF-α production THP-1 cells are preincubated in the presence and absence of BIRB 796 for 30 min. Cell mixture is stimulated with LPS (1 μg/mL final) and incubation continued overnight (18−24 hours) as above. Supernatant is analyzed for human TNF-α by a commercially available ELISA. Data are combined and analyzed by nonlinear regression using a three parameter logistic model to obtain an EC50 value. BIRB 796 is analyzed in each experiment and the 95% confidence intervals for the EC50 are between 16 and 22 nM.

動物実験:

[2]

動物モデル Collagen-induced arthritis in female Balb/c mice
製剤 70% PEG400 (intravenous) or 100% PEG400 (oral)
投薬量 1 mg/kg (intravenous) or 10 mg/kg (oral)
投与方法 Intravenous injection or by oral

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 BIRB 796 (Doramapimod) SDF
分子量 527.66
化学式

C31H37N5O3

CAS No. 285983-48-4
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 106 mg/mL (200.88 mM)
エタノール 106 mg/mL (200.88 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 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea

カスタマーフィードバック (5)


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Rating
Source Blood, 2012, 119(26), 6255-8. BIRB 796 (Doramapimod) purchased from Selleck
Method FACS analysis
Cell Lines B-lymphoid, myeloid cells
Concentrations 400 nM
Incubation Time
Results To further determine the content of functional HSPC in these cultures, it transplanted cells to sublethally irradiated Nod Scid Gamma (NSG) mice. Then, the engrafted cells showed robust repopulation of both the myeloid and lymphoid lineage, when cultured with BIRB796 (400 nM).

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Rating
Source Cancer Lett, 2012, 324(1), 98-108. BIRB 796 (Doramapimod) purchased from Selleck
Method Western blot
Cell Lines HT-29 cells
Concentrations 0.1 uM
Incubation Time 24, 48, 72 h
Results Here it show that in CRC cells pharmacologic inhibition of p38α potentiates the MEK/ERK pathway, irrespectively of the mutational status of the ERK upstream activators RAS and RAF. Indeed, BIRB796 increased phospho-activation of ERK1/2 was observed in BRAF mutant HT-29 cells.

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Rating
Source Int J Cancer, 2014, 134(3), 575-86. BIRB 796 (Doramapimod) purchased from Selleck
Method Western blot
Cell Lines Peripheral blood mononuclear cells
Concentrations 0.1 mM
Incubation Time 30 min
Results It confirmed that the inhibitors were blocking downstream p38 signaling by measuring MK2 phosphorylation in moDC. Treatment with SB203580 or BIRB0796 1.0 mM prevented TLR-induced MK2 phosphorylation, whereas 0.1 mM BIRB0796 did not fully inhibit MK2 activation. BIRB0796 did not affect phospho-p38 activation but ablated ERK phosphorylation.

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Rating
Source Biochem J, 2014, 449(2), 497-506. BIRB 796 (Doramapimod) purchased from Selleck
Method Western blot
Cell Lines NIH 3T3 cells
Concentrations 50 nM
Incubation Time 2 h
Results Therefore it tested BIRB796, an inhibitor structurally unrelated to SB203580 that blocks the ATP-binding site of p38 MAPK. NIH 3T3 cells were pretreated with BIRB796 and then incubated under starvation conditions with or without 10 mM glucose for 2 h. Lipidation of LC3 was analysed by Western blotting. As shown in Figure, BIRB796 repressed the accumulation of LC3-II induced by glucose.

Click to enlarge
Rating
Source BIRB 796 (Doramapimod) purchased from Selleck
Method Western blot
Cell Lines HEK293 cells
Concentrations 0.01-1 μM
Incubation Time 1 h
Results BIRB796 treatment resulted in a reduction of p38 phosphorylation in HEK293 cells.

文献中の引用 (17)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description