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BI-847325

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Chemical Structure| 1207293-36-4 同义名 : -
CAS号 : 1207293-36-4
货号 : A245078
分子式 : C29H28N4O2
纯度 : 99%+
分子量 : 464.558
MDL号 : MFCD28978743
存储条件：

粉末 Keep in dark place,Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 16 mg/mL(34.44 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • Aurora A

    Aurora A (Human), IC50:25 nM

  • Aurora B

    Aurora B (Xenopus laevis), IC50:3 nM

  • Aurora C

    Aurora C (Human), IC50:15 nM

  • MEK2

    MEK2, IC50:4 nM

  • MEK1

    MEK1, IC50:25 nM
描述 Three Homologous Aurora kinases (AK-A, -B, and -C) have overlapping effects on the cell cycle, in particular cytokinesis. AK-A has been implicated in mitotic entry, separation of centriole pairs, bipolar spindle assembly, and alignment of metaphase chromosomes. AK-B is involved in chromosomal biorientation, regulating the association between kinetochores and microtubules, and phosphorylates histone H3 (HH3) which aids chromatin condensation and separation[3]. BI-847325 is an ATP-competitive dual inhibitor of MEK and Aurora kinases with IC50s of 25, 3 and 15 nM for Aurora A, B, and C respectively. BI-847325 can potently inhibit MEK1/2 and Aurora A/B kinases. In a vitro study, C643 cell line was collected, cultured and treated with 15 μM and 34 μM concentrations of BI-847325 for 48 h. MALAT1 gene expression, following BI-847325 treatment was determined and the result showed that the expression of MALAT1 in C643 (p < 0.01) cell line was significantly decreased in comparison with untreated control, suggesting that BI-847325 which inhibits Aurora kinase family could be effective against cancer by regulating the genes involved in cell cycle and apoptosis including MALAT1 and its downstream genes[3]. And in another vitro study, a enzyme, ATP and kinase buffer mixture (30 mL) was added to 10 μL BI-847325 solution for 15 min at room temperature. and 10 mL of peptide mixture was added subsequently for 1 h at room temperature then reaction was stopped for calculation of IC50 values and measurement of Incorporated phosphate, suggesting that BI-847325 possess potent activity for Aurora kinases inhibition. In a cell-cycle analysis, A375 and Calu-6 cell lines were treated with BI-847325 at dose of 50 and 500 nM for 48 h. After fixing and staining, cells were performed cell cycle analysis, indicating that cells treated with BI-847325 at low concentration (50 nM) showed a high percentage of cells in G2–M and polyploid/multinucleated states and low proportion in G1 phase and at high concentrations (500 nmol/L), the proportion of cells in G1 decreased further whereas that in G2–M and polyploid/multinucleated states increased. The result showed that BI-847325 acts as a dual MEK and Aurora kinase inhibitor in these two cell lines. In a vivo study, bearing A375 (BRAFV600E) xenografts mice were orally treated at 10 mg/kg of BI-847325 daily for 10 days. Marked inhibition of MEK and ERK phosphorylation in tumors was observed 2 hours after the last dosing[4].
作用机制 BI-847325 is located in the ATP-binding pocket in the hinge region of both kinases and thus acts as an ATP-mimetic[4].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.15mL

0.43mL

0.22mL

10.76mL

2.15mL

1.08mL

21.53mL

4.31mL

2.15mL
参考文献

[1]Phadke MS, Sini P, et al. The Novel ATP-Competitive MEK/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK Expression. Mol Cancer Ther. 2015 Jun;14(6):1354-64.

[2]Sini P, Gürtler U, et al. Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases. Mol Cancer Ther. 2016 Oct;15(10):2388-2398. Epub 2016 Aug 5.

[3]Samimi H, Haghpanah V, Irani S, Arefian E, Sohi AN, Fallah P, Soleimani M. Transcript-level regulation of MALAT1-mediated cell cycle and apoptosis genes using dual MEK/Aurora kinase inhibitor "BI-847325" on anaplastic thyroid carcinoma. Daru. 2019 Jun;27(1):1-7.

[4]Sini P, Gürtler U, Zahn SK, Baumann C, Rudolph D, Baumgartinger R, Strauss E, Haslinger C, Tontsch-Grunt U, Waizenegger IC, Solca F, Bader G, Zoephel A, Treu M, Reiser U, Garin-Chesa P, Boehmelt G, Kraut N, Quant J, Adolf GR. Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases. Mol Cancer Ther. 2016 Oct;15(10):2388-2398.