AZD1152-HQPA (CAS 722544-51-6)

AZD1152-HQPA is a highly selective ARK-2 inhibitor with IC₅₀ of 0.37 nM. AZD1152-HQPA is the active metabolite of AZD-1152, a potent selective Aurora Kinase B inhibitor. AZD1152 is 50-fold selective for Aurora kinase B over Aurora kinase C and over 1000-fold selective for Aurora kinase B over Aurora Kinase A. (IC50s: aurora-A, 1,369 nmol/L; aurora-B, 0.36 nmol/L; aurora-C, 17.0 nmol/L). It is converted in plasma to the active form AZD1152-HQPA, which has been shown to have antineoplastic activity in a variety of animal models and human cancer cell lines. Aurora kinase B (AURKB), a crucial regulator of malignant mitosis, is involved in chromosome segregation and cytokinesis. AZD1152-HQPA is a selective inhibitor for AURKB activity and currently bears clinical assessment for several malignancies. However, the effect of this drug still needs to be elucidated in neurological malignancies. In this study, we investigated the restrictive potentials of AZD1152-HQPA in U87MG and SK-N-MC. AZD1152-HQPA treatment resulted in growth arrest, modification of cell cycle, and inhibition of colony formation in both cell lines. Furthermore, lower concentrations of AZD1152-HQPA profoundly induced apoptosis in U87GM (p53/p73 wild type) cells in parallel with an upregulation of p53 and its target genes BAX, BAD, APAF1, and PUMA. But remarkably, SK-N-MC (p53/p73 double null) responded to AZD1152-HQPA at much higher concentrations with an upregulation of genes involved in cell cycle progression, induction of excessive endoreduplication, and polyploidy rather than apoptosis. Although SK-N-MC was resistant to AZD1152-HQPA, we did not find a mutation in the coding sequence of Aurora B gene or overexpressions of ABCG2 and ABCB1 as reported previously to be resistance mechanisms. However, our results suggest that p53/p73 status could be an important mechanism for the type of response and resistance of the tumor cells to AZD1152-HQPA. Collectively, inhibition of Aurora kinase B differentially induced cell death and polyploidy via DNA damage response pathways, depending on the status of p53/p73. We suggest p53/p73 could be a key regulator of sensitivity to AZD1152-HQPA and their status should be explored in clinical response to this ongoing drug in clinical trials.