Aurora Kinase Inhibitors - Biotech, Pharma and Life Science Channel
Mitosis, a central event in tumor growth, is highly regulated to ensure accurate and equal segregation of genetic materials from parent cells to daughter cells. Main effectors of this process are mitotic spindles and centrosomes. Disruption of the process results in aneuploidy, and genomic instability renders the cellular condition optimal for apoptosis to occur. The rationale of targeting mitosis in cancer therapy is substantiated by the successful clinical development of tubulin-disrupting agents, such as vinca alkaloids and taxanes.
The coordination of progression through mitosis is mainly orchestrated by protein phosphorylation insured by several serine/threonine kinases of which the three main mitotic kinase families are the cyclin-dependent kinase CDKs), the polo-like kinases (Plks), and the Aurora kinases. Mammals have three Aurora kinases, named Aurora A, B and C. Aurora A has distinct functions while Aurora B and C share same functions, though all three kinases are involved in the control of many processes required for mitosis.
Errors in mitosis can provide a source of the genomic instability that is typically associated with tumorigenesis. Many mitotic regulators are aberrantly expressed in tumour cells. These proteins could therefore make useful therapeutic targets. The kinases Aurora-A, -B and -C represent a family of such targets and several small-molecule inhibitors have been shown to block their function. Not only have these inhibitors advanced our understanding of mitosis, but, importantly, their in vivo antitumour activity has recently been reported.
Members of the Aurora-kinase family have recently emerged as key mitiotic regulators required for genome stability. Furthermore, these serine/threonine kinases are frequently overexpressed in human tumours. For example, Aurora-A is frequently amplified in tumours, indicating that it is important for tumour formation or progression. The Auroras are involved in regulating multiple steps of mitosis, including centrosome duplication, formation of a bipolar mitotic spindle, chromosome alignment on the mitotic spindle and, perhaps most importantly, the fidelity-monitoring spindle checkpoint itself.
As the Auroras are clearly implicated in tumorigenesis, and are also kinases (which makes them amenable to small-molecule inhibition), they are thought to represent promising targets for anticancer drug development. Given the amplification of Aurora-A in tumours and the observation that it can act as a bona fide oncogene, transforming cells when ectopically expressed in vitro, its product has been highlighted as a drug target. Several reports have been published describing the first generation of small-molecule inhibitors of Aurora-kinase activity, and one has shown antitumour activity in in vivo models.
Source; Nat Rev Cancer. 2004;4(12) N Keen, S Taylor
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Taxodium
A plant genus of the family TAXODIACEAE. Members contain taxodione and taxodone, which are diterpenoid quinone methide tumor inhibitors.
Huperzia
A plant genus of the family LYCOPODIACEAE. Members contain huperzine, one of the CHOLINESTERASE INHIBITORS.
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An eph family receptor found primarily in BRAIN and THYMUS. The EphB6 receptor is unusual in that its tyrosine kinase domain shares little homology with other members of this class. The unusual tyrosine kinase domain of this receptor appears to result in its lack of tyrosine kinase activity.
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A family of ribosomal protein S6 kinases that are structurally distinguished from RIBOSOMAL PROTEIN S6 KINASES, 70-KDA by their apparent molecular size and the fact they contain two functional kinase domains. Although considered RIBOSOMAL PROTEIN S6 KINASES, members of this family are activated via the MAP KINASE SIGNALING SYSTEM and have been shown to act on a diverse array of substrates that are involved in cellular regulation such as RIBOSOMAL PROTEIN S6 and CAMP RESPONSE ELEMENT-BINDING PROTEIN.
