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].
BI-847325 细胞实验
Cell Line
Concentration
Treated Time
Description
References
WM793R
300nM–3µM
48 hours
BI-847325 induced cell death in 3D organotypic cell culture models.
Mol Cancer Ther. 2015 Jun;14(6):1354-64.
1205LuR
10nM – 1µM
48 hours
BI-847325 induced significant apoptosis in BRAF-mutant and vemurafenib-resistant melanoma cell lines.
Mol Cancer Ther. 2015 Jun;14(6):1354-64.
WM793
30–300 nM
4 weeks
BI-847325 prevented colony formation in 6 BRAF-mutant melanoma cell lines.
Mol Cancer Ther. 2015 Jun;14(6):1354-64.
1205Lu
1 nM to 30 µM
72 hours
BI-847325 significantly inhibited the growth and survival of BRAF-mutant and vemurafenib-resistant melanoma cell lines.
Mol Cancer Ther. 2015 Jun;14(6):1354-64.
Mammary cancer cells
0.004-30 μmol/L
4 days
Evaluate the antiproliferative activity of BI-847325 on mammary cancer cells, showing high sensitivity
Cancer Res Commun. 2023 Oct 25;3(10):2170-2181.
Colorectal cancer cells
0.004-30 μmol/L
4 days
Evaluate the antiproliferative activity of BI-847325 on colorectal cancer cells, showing high sensitivity
Cancer Res Commun. 2023 Oct 25;3(10):2170-2181.
Bladder cancer cells
0.004-30 μmol/L
4 days
Evaluate the antiproliferative activity of BI-847325 on bladder cancer cells, showing high sensitivity
Cancer Res Commun. 2023 Oct 25;3(10):2170-2181.
Melanoma cells
0.004-30 μmol/L
4 days
Evaluate the antiproliferative activity of BI-847325 on melanoma cells, showing high sensitivity
Cancer Res Commun. 2023 Oct 25;3(10):2170-2181.
Acute myeloid leukemia cells
0.004-30 μmol/L
4 days
Evaluate the antiproliferative activity of BI-847325 on acute myeloid leukemia cells, showing high sensitivity
Cancer Res Commun. 2023 Oct 25;3(10):2170-2181.
Acute lymphocytic leukemia cells
0.004-30 μmol/L
4 days
Evaluate the antiproliferative activity of BI-847325 on acute lymphocytic leukemia cells, showing high sensitivity
Cancer Res Commun. 2023 Oct 25;3(10):2170-2181.
SW1736
34 µM
48 hours
BI-847325 inhibited the function of MEK1/2 and AURKB by decreasing phospho-ERK1/2 and phospho-Histone H3 levels, induced thyroid differentiation markers NIS and Tg, promoted apoptosis, and reduced multidrug resistance, cell cycle progression, proliferation, angiogenesis, and invasion.
Cancer Cell Int. 2022;22(1):388.
C643
15 µM
48 hours
BI-847325 inhibited the function of MEK1/2 and AURKB by decreasing phospho-ERK1/2 and phospho-Histone H3 levels, induced thyroid differentiation markers NIS and Tg, promoted apoptosis, and reduced multidrug resistance, cell cycle progression, proliferation, angiogenesis, and invasion.
Cancer Cell Int. 2022;22(1):388.
SW1736 cells
34 μM
48 hours
After BI-847325 treatment, MALAT1 gene expression was significantly downregulated (p <0.001), miR-363-3p expression was significantly upregulated (p <0.0001), Mcl1 expression was not significantly downregulated, and cyclin D1 expression was significantly downregulated (p <0.001).
Daru. 2019;27(1):1-7.
C643 cells
15 μM
48 hours
After BI-847325 treatment, MALAT1 gene expression was significantly downregulated (p <0.01), miR-363-3p expression was significantly upregulated (p <0.0001), Mcl1 expression was significantly downregulated (p <0.001), and cyclin D1 expression was significantly downregulated (p <0.01).
Daru. 2019;27(1):1-7.
A549 lung cancer cell line
30 μM
72 hours
To evaluate the growth inhibitory effect of BI-847325 on A549 cells, showing a GI50 of 30 μM.
Med Oncol. 2022 Jul 14;39(10):144.
SW1736
1–64 μM
24–72 h
Evaluate the cytotoxicity of BI-847325 in 3D culture system, showing an IC50 value of 34 μM
Thyroid Res. 2021 Dec 3;14(1):27.
C643
1–64 μM
24–72 h
Evaluate the cytotoxicity of BI-847325 in 3D culture system, showing an IC50 value of 15 μM
Thyroid Res. 2021 Dec 3;14(1):27.
SW1736
0.125–8 μM
24–72 h
Evaluate the inhibitory effect of BI-847325 on cell proliferation, showing an IC50 value of 4 μM
Thyroid Res. 2021 Dec 3;14(1):27.
C643
0.125–8 μM
24–72 h
Evaluate the inhibitory effect of BI-847325 on cell proliferation, showing an IC50 value of 2 μM
Thyroid Res. 2021 Dec 3;14(1):27.
BI-847325 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB severe combined immune deficient (SCID) mice
1205Lu and 1205LuR xenograft models
Oral gavage
70 mg/kg
Once weekly for 65 days
BI-847325 significantly suppressed the growth of BRAF-mutant and vemurafenib-resistant human melanoma xenografts.
Mol Cancer Ther. 2015 Jun;14(6):1354-64.
Nude mice
Subcutaneous xenograft models
Oral
40 and 80 mg/kg
Once weekly for 3 or 4 weeks
Evaluate the antitumor activity of BI-847325 in vivo in various cancer models, showing high activity in colorectal, gastric, mammary, and pancreatic cancer models
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