A selective Aurora kinase B inhibitor
Barasertib, previously known as AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a potent aurora kinase inhibitor, which is resulted from rapid phosphatase-mediated cleavage of the precursor, AZD1152, in serum following parenteral administration in vivo. It shows inhibitory effects against a broad range of aurora kinases, including aurora A kinase (AKB), aurora B kinase (ABK), and aurora C kinase (ACK) with inhibition constant (Ki) of 1369 nM, 0.36 nM, and 17.0 nM respectively, as well as the FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation. Barasertib has demonstrated anti-tumor activity against a range tumor cell lines including those of leukaemic acute myeloid leukemia (AML) origin.
Reference
[1].Martin Grundy, Claire Seedhouse, Nigel H Russell and Monica Pallis. P-glycoprotein and breast cancer resistance protein in acyte myeloid leukaemia cells treated with the aurora-B kinase inhibitor barasertib-Hqpa. BMC Cancer 2011, 11:254
[2].Mike Dennis, Michelle Davies, Stuart Oliver, Roy D’Souza, Laura Pike, and Paul Stockman. Phase I study of the aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia. Cancer Chemother Pharmacol (2012) 70:461-469
| Cell experiment: [1] | |
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Cell lines |
HL-60 cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
25 nM, 72 hours |
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Applications |
The cells exhibited increased DNA contents of 4N and 8N, indicative of polyploidy, within 24–48 h of treatment. After 48–72 h, barasertib-HQPA induced apoptotic cell death, as detected by an increased sub-G1 population compared for that of untreated cells. The induction of polyploidy was obvious at 24–48 h, and thereafter, the nuclei showed morphology typical of apoptosis, such as nuclear fragmentation and condensation. These observations were in accordance with the ?ndings of the ?ow cytometric analysis. |
| Animal experiment: [2] | |
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Animal models |
Female nude mice injected with SW620, Colo205 or HCT116 cells |
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Dosage form |
Subcutaneous injection, 150 mg/kg/day, minipump infusion over 48 h |
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Applications |
In SW620, HCT116 and Colo205 xenografts significant tumor growth inhibitions of 79% (P<0.001, day 23), 60% (P<0.001, day 25) and 81% (P<0.05, day 21) were observed, respectively. Colo205 xenografts appeared the most sensitive to treatment with a mean tumor volume (± SEM) on day 21 after cell implantation, of 0.42±0.19 cm3 for the barasertib group compared to 2.24±0.75 cm3 (P<0.05) for the vehicle control animals. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1] Yamauchi T, Uzui K, Shigemi H, et al. Aurora B inhibitor barasertib and cytarabine exert a greater-than-additive cytotoxicity in acute myeloid leukemia cells. Cancer science, 2013, 104(7): 926-933. [2] Alferez D G, Goodlad R A, Odedra R, et al. Inhibition of Aurora-B kinase activity confers antitumor efficacy in preclinical mouse models of early and advanced gastrointestinal neoplasia. International journal of oncology, 2012, 41(4): 1475-1485. | |
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