[Description]:
AZD1152 is a pro-drug of Barasertib-hQPA, which is a highly selective Aurora B inhibitor with IC50 of 0.37 nM in a cell-free assay.
[Related Catalog]:
[Target]
[In Vitro]
AZD1152 displays >3000-fold selectivity for Aurora B as compared with Aurora A which has an IC50 of 1.368 μM. AZD1152 has even less activity against 50 other serine-threonine and tyrosine kinases including FLT3, JAK2, and Abl. AZD1152 inhibits the proliferation of hematopoietic malignant cells such as HL-60, NB4, MOLM13, PALL-1, PALL-2, MV4-11, EOL-1, THP-1, and K562 cells with IC50 of 3-40 nM, displaying appr 100-fold potency than another Aurora kinase inhibitor ZM334739 which has IC50 of 3-30 μM. AZD1152 inhibits the clonogenic growth of MOLM13 and MV4-11 cells with IC50 of 1 nM and 2.8 nM, respectively, as well as the freshly isolated imatinib-resistant leukemia cells with IC50 values of 1-3 nM, more significantly compared with bone marrow mononuclear cells with IC50 values of >10 nM. AZD1152 induces accumulation of cells with 4N/8N DNA content, followed by apoptosis in a dose- and time-dependent manner[1]. AZD1152 causes significant accumulation of cells with 4N/8N DNA content in KMS12 and U266 and induces apoptosis in KMS18 and U266. AZD1152 in combination with DEX, has negative effects on cell viability in comparison with single agent in PMI8226, KMS11 and U266[3].
[In Vivo]
Administration of AZD1152 (25 mg/kg) alone markedly suppresses the growth of MOLM13 xenografts, confirmed by the observation of necrotic tissue with infiltration of phagocytic cells[1]. In addition, AZD1152 (10-150 mg/kg/day) significantly inhibits the growth of a variety of human solid tumor xenografts, including colon, breast, and lung cancers, in a dose-dependent manner[2]. AZD1152 (25 mg/kg/day) treatment reduces xenograft levels such that they are slightly lower levels than after the first round of treatment, but this is not statistically significant indicating that residual cells might be more resistant to a second cycle of AZD1152[4].
[Cell Assay]
Approximately 1×105 cells in RPMI media with 10% FBS media are plated per well in a treated 96-well plate at 24-h intervals for up to 120 h (in triplicate for each time-point). For each timepoint, 20 μL of MTS reagent [3-(4,5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium, inner salt] solution is added to each well and incubated at 37°C for 4 h. The plate absorbance is read at 490 nm on a 96-well spectra max 190 Plate Reader using Softmax Pro 4.8 Software. MTS solution is added to media-only wells to correct for background. Setting the control cells at 100% viability, the viability of cells treated with various concentrations of siRNA or drug is determined and graphed using MS Excel.
[Animal admin]
Female immune-deficient BALB/c nude mice at 4 weeks of age are purchased from JAPAN SLC and are maintained in pathogen-free conditions with irradiated chow. Animals are bilaterally, subcutaneously injected with 2×106 MOLM13 cells/tumor in 0.1 mL Matrigel. When MOLM13 cells formed palpable tumors, mice are divided randomLy into control (n=5) and treatment groups (n=5), and treatment is begun. AZD1152 (5 or 25 mg/kg) with or without vincristine (0.2 mg/kg) is given to mice by intraperitoneal injection 4 times a week or every another day, respectively. Daunorubicin (1 mg/kg) is given to mice by intraperitoneal injection 6 times during 2 weeks of treatment either alone or in combination with AZD1152 (5 mg/kg). The dose of these agents is determined by our preliminary studies. Control diluent is given to the untreated control mice. Body weight and tumors are measured twice a week. Tumor sizes are calculated. At the end of the experiment, animals are killed by CO2 asphyxiation and tumor weights are measured after their careful resection. Tumor tissue is collected for analysis.
[References]
[1]. Yang J, et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood. 2007 Sep
[2]. Wilkinson RW, et al. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res. 2007 Jun 15;13(12):3682-8.
[3]. Evans RP, et al. The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma. Br J Haematol. 2008 Feb;140(3):295-302.
[4]. Oke A, et al. AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res. 2009 May 15;69(10):4150-8.
[Related Small Molecules]