生物活性

• 靶点

  Aurora Kinase C IC50:15nM

  Aurora Kinase A IC50:25nM

  MEK1 IC50:25nM

  Aurora Kinase B (Xenopus laevis) IC50:3nM

  MEK2 IC50:4nM

• 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 (BRAF^V600E) 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].

• 动物研究
  剂量	Mice: 10 mg/kg/q.d., 20 mg/kg/q7d[2] (p.o.), 70 mg/kg/week[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[2] Dose 10 mg/kg Administration p.o. Cmax 377 ± 87 nmol/L AUC 3700 ± 1600 nmol·h/L

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01324830	Neoplasms	Phase 1	Completed	-	Belgium ... more >> 1287.1.3201 Boehringer Ingelheim Investigational Site Bruxelles, Belgium 1287.1.3202 Boehringer Ingelheim Investigational Site Leuven, Belgium Collapse <<

• 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.