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].
搜索
