BMS-345541(free base) 是 IKK 催化亚基的选择性抑制剂 (IKK-2 IC50=0.3 μM, IKK-1 IC50=4 μM)。 BMS-345541（游离碱）结合在 IKK 的变构位点。
BMS-345541(free base) is a selective inhibitor of IKK-1 and IKK-2 with IC50 value of 4μM and 0.3μM, respectively [1].
IKK is also known as nuclear factor kappa-B kinase subunit inhibitor and involves in cytokine-activated intracellular signaling pathways. IKK-1 and IKK-2 are members of IKK family. It has been reported that IKK-2 plays a pivotal role in brain cells following a stroke [2] [3].
BMS-345541 is a potent IKK inhibitor and has a highly selective activity compared with other kinases. When tested with THP-1 monocytic cells, pre-incubation with BMS-345541 inhibited TNF-α-stimulated IKK phosphorylation and reduced a variety of cytokines production including TNF-α, IL-1β, IL-8, and IL-6 [1]. In 4 human glioma cell lines, BMS-345541 treatment significantly blocked cell proliferation (80%-95%) at the concentration of 10 μM or higher and also inhibited IL-8 expression in a dose dependent manner (IC50>2 μM) [2]. And similar result of BMS-34551 inhibition on IKK which induced cell apoptosis was verified in human melanoma cell lines SK-MEL-5, Hs 294T, and A375 [3].
In 18-22g female BALB/c mice model, administration of BMS-345541 inhibited TNF-αproduction in a dose-dependent manner, ~50% inhibition was seen when used the concentration of 10 mg/kg and near complete inhibition was seen at a dose of 100 mg/kg [1].
参考文献:
[1].?? ?Burke, J.R., et al., BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J Biol Chem, 2003. 278(3): p. 1450-6.
[2].?? ?Du, Z., et al., Inhibition of type I interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1. J Interferon Cytokine Res, 2012. 32(8): p. 368-77.
[3].?? ?Yang, J., et al., BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathways. Clin Cancer Res, 2006. 12(3 Pt 1): p. 950-60.
| Cell experiment [1]: | |
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Cell lines |
THP-1 cells |
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Preparation method |
The solubility of this compound in DMSO is >70mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
1-100μM for 1 h |
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Applications |
In THP-1 cells, only the stimulus-induced phosphorylation of IκB was inhibited by BMS-345541 whereas other signal transduction cascades were unaffected. BMS-345541 inhibited IKK (Iκ B kinase) in cells in the micromolar range and was effective in THP-1 cells at inhibiting the stimulated production of a number of cytokines from THP-1 cells including TNF, IL-1, IL-8, and IL-6. |
| Animal experiment [2]: | |
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Animal models |
18–22-g female BALB/c mice |
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Dosage form |
2mg/kg (1 ml/kg) intravenous bolus or 10 mg/kg (5 ml/kg) peroral gavage. |
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Application |
In BALB/c mice, BMS-345541 dose-dependently inhibited LPS (intraperitoneal)-induced serum TNF production in mice at doses in the 3 to 100 mg/kg range. Approximately 50% inhibition was observed at 10 mg/kg, near complete inhibition of serum TNF was observed at a dose of 100 mg/kg BMS-345541. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Burke, J.R., et al. BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J Biol Chem, 2003. 278(3): p. 1450-6. | |
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