In plants altered expression of Aurora kinases results in im

In plants, altered expression of Aurora kinases results in impaired meiotic divisions followed by the formation of aneuploid or polyploid progenies [21]. This observation is interesting from an evolutionary point of view because it can be assumed that, during evolution, the influence of biotic and abiotic factors on the activity of Aurora kinases resulted in formation of aneuploids or polyploids that served as a basis for the formation of new species. In addition, this knowledge can be used for applied research because it has been shown that manipulation of Aurora kinase activity by Aurora inhibitors efficiently resulted in the formation of aneuploids and polyploids [21]. Therefore, Aurora kinase inhibitors can be introduced into breeding practices for the generation of aneuploids and polyploids, in addition to colchicine which is intensively used by breeders at present. Moreover, detailed studies in this direction might help in understanding the problem of plant genome stability (see Outstanding Questions). Compared to animal and yeast Kingdoms, the plant community is merely starting to grasp the impact of Aurora kinases on plant development. The fact that many plant-specific phenotypes occur in aurora mutants, and that animal and plant Aurora kinases do show functional divergence, makes it interesting to further functionally unravel these key mitotic kinases.
Acknowledgment
Introduction The Aurora family of serine/threonine kinases plays important roles during mitosis and meiosis. This kinase family consists of three paralogues, designated as Aurora A, B, and C, which show quite different features as regards to their expression, cellular localization, and function. Aurora A is localized in the centrosome and is important for mitotic processes. It is involved in the mitotic entry, centrosome maturation, and spindle dynamics. Aurora B adjusts the chromosomal bi-orientation, regulates the association between kinetochores and microtubules, and controls cytokinesis. Aurora B phosphorylates histone H3 at Ser10, which then regulates Adenine sulfate condensation and separation.3, 4 Aurora C exhibits functions similar to those of Aurora B during meiosis. Aurora kinases are over-expressed in various tumor cell-lines, suggesting that these kinases might play a crucial role in cancer progression. There is a correlation reported between the overexpression of Aurora kinases and various tumors such as breast cancer, colorectal cancer, and acute myeloid leukemia, leading to considerable interest in Aurora kinases as possible anticancer targets. A number of Aurora kinase inhibitors have been identified as chemotherapeutic candidates, and several compounds are undergoing preclinical and clinical trials. Aurora A and B share most of their primary protein structures, 71% of the whole protein. Regardless of the structural similarity between Aurora A and B, they perform distinct roles in the mitotic process. The consequences of Aurora A and B inhibition are quite different, and the proliferating cells are more sensitive to the inhibition of Aurora B than that of Aurora A. The important differences between the structures of Aurora A and B kinases exist at the residues Arg175, Glu177, and Lys180 of Aurora B kinase vs Lue215, Thr217, and Arg220 of Aurora A kinase. At the active site of the Aurora kinases, Glu177 in Aurora B kinase corresponds to a smaller amino acid, Thr, in Aurora A kinase. This results in a difference in the size, shape, and charge of the binding cavity at the active site. By targeting this residue, some inhibitors such as barasertib as a representative selective Aurora B kinase inhibitor, can acquire subtype selectivity. In a former study, we identified aminobenzoxazole derivatives as lead compounds of Aurora B kinase inhibitors, and the most potent compound showed a half maximal inhibitory concentration (IC50) value of 0.6μM. In our endeavor to improve the potency of the lead compound, detailed molecular modeling was performed. The results brought us to become aware of a lipophilic cavity which aromatic heterocycle of hinge binder positioned in and is composed of hydrophobic amino acid residues such as Val, Lue, and Ala (Fig. 1A, B). It is implied that enhancing the lipophilic property of the aromatic heterocycle of the inhibitor can increase its affinity to Aurora B kinase. Hence, the benzoxazole scaffold was altered to a benzothiazole one, which is derived by replacing the oxygen atom of the benzoxazole core with sulfur (Fig. 1C). This could increase the lipophilicity of the molecule without any significant change in shape. In this study, we described the SAR of a novel series of aminobenzothiazole derivatives as Aurora B kinase inhibitors and their inhibitory effect on the phosphorylation of Histone H3 and cell cycle progression.