ipatasertib Aurora A the polar kinase is located

Aurora A the ’polar kinase’ is located at the centrosome and is required for its maturation, division, for the mitotic spindle assembly and entry into mitosis., Mutation or transcriptional silencing of Aurora A impairs centrosome maturation and separation, leads to mono/multipolar spindles, to delayed mitotic entry and even to apoptosis in some experiments., On the other hand, amplification of the AURKA gene and overexpression of Aurora A protein causes multipolar spindles, cytokinesis failure, thus chromosomal aberrations and increased resistance to apoptosis in cellular, and in models. Indeed, AURKA gene amplification and Aurora A protein overexpression is a common phenomenon in various human tumors and correlates with poor prognosis., , , , Aurora B the ’equatorial kinase’ is required for chromosome condensation in the prophase, for the spindle assembly checkpoint in the inner centromere regions, for chromosome segregation during metaphase and for cytokinesis itself at the central spindle. Depletion or inhibition of Aurora B kinase activity causes omission of cytokinesis, multi-nucleated polyploid ipatasertib and ultimately apoptosis., , The AURKB gene is not commonly amplified, or mutated, however overexpression of Aurora B protein has been reported in many cancer cell lines and tumor types. The notion that overfunctioning Aurora A and B kinases can significantly contribute to the growth of malignancies, led to the development of several Aurora A and/or Aurora B inhibitors., ,
The Aurora kinases are a family of cell-cycle regulated serine/threonine kinases which are primarily active during mitosis. These homologous kinases effect distinct processes via differential expression, localization and interaction partners. Aurora A localizes at the centrosome during interphase, and localizes at mitotic poles and to the spindle throughout mitosis. Aurora A regulates progression of mitosis and promotes centrosome maturation. Aurora B localizes to centromeres during metaphase as part of the chromosomal passenger complex (CPC) and remains associated with the central mitotic spindle during anaphase. The CPC regulates chromosome condensation, via phosphorylation of histone H3, the spindle assembly checkpoint (SAC) and cytokinesis. Unlike Aurora A and B, Aurora C is not expressed in all dividing cells, as its primary role is in male meiosis during spermatogenesis., The Aurora kinases are implicated in a variety of hematological and solid cancers. Aurora A and B are frequently overexpressed in cancer, and have been associated with aneuploidy and poor prognosis., Aurora C has also been show to function as an oncogene and overexpression has been reported in thyroid cancer tissues. The Aurora kinases have therefore become attractive drug targets with more than ten Aurora inhibitors undergoing clinical trials. In solid tumors, on-target bone marrow toxicity has precluded the use of Aurora inhibitors in cancer therapy. This is hypothesized to be due to the slower proliferation rate of cells in solid tumors relative to those in the bone marrow, and the requirement for drug exposure through several cell cycles before the maximal cytotoxic effects are realized. Acute hematological tumors, such as Acute Myeloid Leukaemia (AML), have higher proliferation rates and have shown more promising response rates to Aurora kinase inhibitors in the clinic., , Many Aurora kinase inhibitors developed to date display poly-pharmacology, targeting numerous kinases. Whilst this may contribute to clinical efficacy, it does not facilitate detailed study of Aurora kinase mediated signaling and cellular processes. Recently, Carry et al. reported an exquisitely selective pan-Aurora inhibitor, SAR156497. This compound displayed efficacy but had a narrow therapeutic window in colon adenocarcinoma xenograft studies. SAR156497 was used as a control compound in our experiments, is one of the most selective cell permeable pan-Aurora inhibitors described to date.