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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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AZD1152-HQPA (Barasertib) is a highly selective Aurora B inhibitor with IC50 of 0.37 nM. |
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Targets
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Aurora B |
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IC50 |
0.37 nM [1] |
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In Vitro
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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 ~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] |
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In Vivo
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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] |
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Clinical Trials
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A Phase I study to assess the safety and tolerability of AZD1152-HQPA in combination with low dose cytosine arabinoside (LDAC) in patients with acute myeloid leukaemia (AML) has been completed. |
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Features
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Combination Therapy
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Description
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AZD1152 (3 nM) synergistically enhances the antiproliferative activity of conventional antileukemia agent vincristine (0.3 μM) or daunorubicin against the MOLM13 and PALL-2 cells, with the increased inhibition from 35% in vincristine alone to 80% in combination, which is consistent with the augmented cleavage of PARP. [1] AZD1152 (5 mg/kg) in combination with vincristine (0.2 mg/kg) or daunorubicin (1 mg/kg) completely inhibits the proliferation of human MOLM13 leukemic xenografts, more potently than that of any drug treatment alone with inhibition only by ~50%. [1] |
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Protocol
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Cell Assay
[1]
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| Cell Lines |
HL-60, NB4, MOLM13, PALL-2, MV4-11, EOL-1, and K562 cells |
| Concentrations |
Dissolved in DMSO, final concentrations ~100 nM |
| Incubation Time |
24 or 48 hours |
| Methods |
Cells are exposed to various concentrations of AZD1152 for 24 or 48 hours. Cell proliferation is measured by 3H-thymidine uptake (isotope added 6 hours before harvest), and the concentration that induced 50% growth inhibition (IC50) is calculated from dose-response curves. Cell cycle analysis is performed by flow cytometry. Cell apoptosis is measured by annexin V–FITC apoptosis detection kit. |
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Animal Study
[1]
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| Animal Models |
Female immune-deficient BALB/c nude mice subcutaneously injected with MOLM13 cells |
| Formulation |
Dissolved in 3M Tris, pH 9.0, at a concentration of 2.5 mg/mL |
| Doses |
5 or 25 mg/kg |
| Administration |
Intraperitoneal injection 4 times a week or every another day |
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