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  • Aurora B is also very important in

    2023-01-24

    Aurora-B is also very important in proper cytokinesis. In the absence of Aurora-B mediated phosphorylation of Ser72 in vimentin, the two daughter cells remain attached to each other through bridges of cytoplasm; cytokinesis fails [31]. Other Aurora-B dependent proteins that are important for cytokinesis include MgcRacGap, MKLP-1 and condensin 1 [32]. Fig. 2 gives an overview of Aurora-B functions and interactions.
    Aurora-C The Aurora-C gene lies within a region of chromosome 19q13 and was only detected in testis [33], [34]. Aurora-C was first thought to be involved in meiotic spindle formation [35] and its localization was restricted to centrosomes from PRX-08066 through to cytokinesis [34], [2]. It was recently discovered that Aurora-C, like Aurora-B, is activated by INCENP. Increased expression of both Aurora-C and INCENP will lead to increased phosphorylation of histone H3, an Aurora-B substrate [5], [36]. This observation lead to the hypothesis that Aurora-C is a chromosome passenger protein and can act in a similar fashion as Aurora-B, although little is known about its functional role. Nevertheless, Aurora-C was until now never demonstrated in somatic cells and its expression is restricted to the testis [2].
    Aurora kinase inhibitors
    Pre-clinical data Several Aurora kinase inhibitors have been studied in vitro and invivo. Table 1 shows the different IC50 values for several Aurora kinase inhibitors tested.
    Clinical (phase I) studies Several drugs with promising pre-clinical results have now reached clinical phase I testing. Amongst them, MK-0457 (VX-680) was studied [56] in a total of 16 patients with refractory solid tumors using a 5-day continuous infusion every 28 days (doses 0.5–12mg/m2/h). DLT, consisting of asymptomatic neutropenia for more than 5 days was observed at 12mg/m2/h. Currently 10mg/m2/h is under investigation to establish the MTD. In three patients a disease stabilization could be observed. From pre-clinical observations MK-0457 is also known for its activity against cells expressing wild-type or mutated BCR-ABL, including the T3151 BCR-ABL mutation known for its ability to mediate resistance to drugs including imatinib, nilotinib, and dasatinib. In a phase I dose escalating study performed by Giles et al. [57] MK-0457 was given in a 5-day continuous infusion every 2–3 weeks. In three patients included in this study, known for their T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphocytic leukemia (ALL) promising antitumor activity was noted without significant adverse events. Whether this antitumor activity can be attributed to Aurora kinase inhibition or to Janus kinase-2 (JAK-2), another feature of MK-0457, remains to be established. In conclusion, MK-0457 is well tolerated even in heavily pre-treated patients. MLN8054, a selective inhibitor of Aurora-A kinase was given orally in a phase I clinical trial as capsules once daily for 7 consecutive days every 21 days [58]. Twenty-two patients were enrolled to evaluate doses of 5–40mg/day. The main observed side effect was grade 2/3 somnolence (3pts at 20mg/day and 2/4pts at 40mg/day) which can be attributed to the binding of the agent to the gamma-aminobutryic acid alpha 1 benzodiazepine (GABAA α1 BZD) receptor. In an attempt to reduce these benzodiazepine-like CNS effects a multiple daily dosing schedule was studied. Again somnolence was the only observed side effect (2/4pts at 55mg/day) and MTD was set at 45mg/day. Skin biopsies taken to establish the drugs mechanism of action by assessing inhibition of Aurora-A kinase in the skins epithelial cells were obtained before and 6h after the first dose but revealed no accumulation of cells in mitosis as would have been with inhibition of the target. Since MLN8054 requires 5–7 days of dosing to reach steady-state concentrations and in pre-clinical studies Aurora-A inhibition is known to be time dependent, the dosing schedule in this study (7 days on, 14 days off) might not be the most appropriate to achieve sustained Aurora kinase A inhibition. Therefore the study was amended [59]. An additional 39 patients were treated, evaluating dose levels 25–55mg/day in four divided doses (QID) for 7 days and 55–80mg-day in QID doses for 7–21 days with the addition of methylphenidate (5–10mg) to reduce somnolence. Patients received a median of 2 cycles (range: 1–14) and the MTD was set at 30mg/day for QD dosing, 45mg-day for QID dosing and 60mg/day for QID dosing plus methylphenidate. In all dosing schedules, somnolence was the predominant side effect, usually starting in the 1st week of dosing. No significant myelosuppression or mucositis were seen. In 52 patients paired pre-treatment and post-treatment skin biopsies were available showing accumulation of mitotic cells, a feature consistent with Aurora-A inhibition. No objective responses were seen, however three patients achieved disease stabilization for more than 6 cycles. Another phase I study [60] assessed the pharmacodynamic effect of MLN8054 on skin and tumor biopsies pre-treatment and post-treatment (day 7). MLN8054 was administered orally in cycles of 7–21 days (25–80mg/day QID) followed by a 14-day resting period. Of the 63 paired skin biopsies, 44 showed an increase in mitotic counts consistent with Aurora-A inhibition. Paired tumor biopsies were available in 10 patients. A reduction in spindle bipolarity and chromosome alignment, consistent with Aurora-A inhibition was observed providing proof of concept of MLN8054 in patient skin and tumor tissue. In a phase I study by Cervantes et al. [61], MLN8054 was given once daily (QD) on days 1–5 and 8–12 in a 28-day cycle (first two cohorts, 10 and 20mg) and in four divided doses (QID) on days 1–14 (25–80mg/day). From 45mg onwards, methylphenidate 5–15mg was co-administered. A total of 43 patients were treated with MLN8054 with a median of 1 cycle (range: 1–10). Consistent with the findings in the other studies somnolence constituted the main DLT. PRX-08066 In addition, transient grade 3 rise in liver enzymes grade 2 mucositis, neutropenia and alopecia were observed. Both skin and tumor biopsies showed accumulation of mitotic cells, especially in the higher dose levels.