Aurora Kinase

Aurora Kinase

The Aurora kinase family comprises of cell cycle-regulated serine/threonine kinases important for mitosis. Their activity and protein expression are cell cycle regulated, peaking during mitosis to orchestrate important mitotic processes including centrosome maturation, chromosome alignment, chromosome segregation, and cytokinesis. In humans, the Aurora kinase family consists of three members; Aurora-A, Aurora-B, and Aurora-C, which each share a conserved C-terminal catalytic domain but differ in their sub-cellular localization, substrate specificity, and function during mitosis. In addition, Aurora-A and Aurora-B have been found to be overexpressed in a wide variety of human tumors.

Aurora kinases are serine threonine kinases that play important roles during the cell cycle. The cell cycle is a highly regulated process monitored by several important factors, including cyclins and associated cyclin-dependent kinases, growth factor signalling and nutrient availability, among others. The cell cycle divided into two major stages: interphase and M phase. Interphase includes the G1, S and G2 phases, during which cell growth, DNA replication and chromosome duplication occur. M phase includes mitosis and cytokinesis.

At present, three aurora kinase isoforms have been identified in mammalian cells: Aurora kinase A (Aurora-A), Aurora kinase B (Aurora-B) and Aurora kinase C (Aurora-C). All three proteins share a similar structure with an N-terminal regulatory domain and a C-terminal catalytic domain followed by a short C-terminal extension. The regulatory domain is highly variable and is probably involved in substrate binding and cellular localization. On the other hand the kinase domain is conserved between the three family members and shares more than 70% homology. The three Aurora kinases mediate key processes during mitosis ranging from mitotic entry to cytokinesis.

Although all three Aurora kinases are involved in cell division, the specific functions of each kinase vary. Aurora A, but not B or C, regulates centrosome maturation and separation and bipolar spindle assembly. Aurora B controls cytokinesis and chromosome bi-orientation as a member of the chromosome passenger complex. Aurora C coordinates meiotic spindles in spermatogenesis, while also cooperating with Aurora B to regulate mitotic chromosome dynamics.

The Aurora kinases are strongly linked to the development and progression of human cancers and therefore their expression in different tumor samples and cell lines has been investigated. The AurA gene is located to the 20ql3 region of the genome which is amplified in many human tumors and elevated protein levels can also be observed in many cancers. The AurB gene is located to the 17pl3.1 region. This region is rarely altered in human tumors but protein levels are frequently increased. Both AURKA and AURKB are not bona fide oncogenes since overexpression of AurA or AurB does not transform cells in vitro or enhance tumor formation in vivo. However both AurA and AurB can enhance the effect of other oncogenic mutations to advance tumor formation. Finally AurC expression could be confirmed for some tumors but by now no function for AURKC in tumorigenesis has been reported.

The first Aurora kinase inhibitor was described in 2003 by the group of Stephen Taylor. In thefollowing years more than 30 drugs were developed by different companies and researchers alike and more than 10 of the developed compounds are being tested in clinical trials. Aurora kinase inhibitors can be subdivided into three groups. The first group of inhibitors inactivates AurA and AurB simultaneously (e.g. ) and the third group specifically targets AurB (e.g. AZD1152). Aurora kinase inhibitors that have progressed through preclinical testing and into phase I or phase II trials include the Aurora A inhibitors MLN8054, PF-03814735, AS703569, MK-0457, MK-5108, MSC1992371A, and the Aurora B inhibitors AT9283 and PHA-739358. Recently, a number of studies have examined the activities of the Aurora A inhibitor MLN8237 and the Aurora B inhibitor AZD1152 (Barasertib).

Reference:

Warner, Steven Lawrence. "Targeting the Aurora Kinases to Treat Pancreatic Cancer." (2005).

Marxer, Miriam. New insights into the physiological functions and anti-cancer drug potential of aurora kinases. Diss. 2012.

Jayanthan, Aarthi Anita. Aurora Kinase Inhibition as a Novel Therapeutic Approach for the Treatment of Refractory Pediatric and Infant Leukemia. Diss. University of Calgary, 2014.

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