Aurora kinases regulate cell cycle transit from G2 through cytokinesis, and thus are targets in cancer therapy. [1] There are three mammalian aurora kinase genes, encoding aurora A, B and C. Intense investigation has focused on aurora A and B as they appear to play a role in oncogenesis [2] with aurora A identified as a low penetrance tumor susceptibility gene in mice and humans. [3] Aurora kinases could be potential targets for novel small-molecule enzyme inhibitors.
A new approach to inhibiting cancer growth that shows great promise for structure-based drug development is targeting enzymes central to cellular mitosis. [4] Aurora kinases, so named because the scattered mitotic spindles generated by mutant forms resemble the Aurora Borealis, have gained a great deal of attention as possible anticancer drug targets. [5] [6] The Aurora enzymes are particularly significant because they are involved in a direct path to the nucleosome by phosphorylating histone H3. [7] [8] Furthermore, Aurora kinases are known to be oncogenic and overexpressed in various forms of cancerous growth, including leukemia, colon cancer, prostate cancer [9] and breast cancer [10] tumors. [11]
So far three Aurora-kinase inhibitors have been described: ZM447439, [12] hesperadin [13] [14] and VX-680. The last is in advanced stages (Phase II clinical trial) of a joint drug development by Vertex Pharmaceuticals's VX-680 (Sausville, 234, last posted on 12/18/06) and Merck & Co., [15] although the Phase II clinical trial was suspended in November, 2007 due to QT prolongation observed in one patient in Phase I trial.
The structure and active site of Aurora-2-adenosine complex has been determined. [16] The hinge (yellow), glycine-rich loop (blue), and activation loop (red) are key features of the protein kinase fold involved in binding adenosine. The protein backbone atoms of residues Glu-211, Ala-213 in the hinge region of Aurora-2, and the sidechain of residue Trp-277, located in the activation loop, bind adenosine through specific hydrogen bonds. There are no hydrogen bonds between the 2'-OH or 3'-OH groups of the ribose moiety and Aurora-2. Residues Lys-162 and Asp-274 are essential for Aurora-2 kinase activity but do not hydrogen bond to each other as seen in crystal structures of several other protein kinases.[ citation needed ]
The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.
Aurora kinases are serine/threonine kinases that are essential for cell proliferation. They are phosphotransferase enzymes that help the dividing cell dispense its genetic materials to its daughter cells. More specifically, Aurora kinases play a crucial role in cellular division by controlling chromatid segregation. Defects in this segregation can cause genetic instability, a condition which is highly associated with tumorigenesis. The first aurora kinases were identified in Drosophila melanogaster, where mutations led to failure of centrosome separation with the monopolar spindles reminiscent of the North Pole, suggesting the name aurora.
The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated check point can lead to cellular transformation and disease states such as cancer
Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.
A serine/threonine protein kinase is a kinase enzyme that phosphorylates the OH group of serine or threonine. At least 125 of the 500+ human protein kinases are serine/threonine kinases (STK).
Aurora B kinase is a protein that functions in the attachment of the mitotic spindle to the centromere.
Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.
Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene.
Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.
In enzymology, a polo kinase is a kinase enzyme i.e. one that catalyzes the chemical reaction
Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene. It is one of the many spindle assembly factors that play a key role in inducing microtubule assembly and growth during M phase.
Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the LATS1 gene.
Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene.
Large tumor suppressor kinase 2 (LATS2) is an enzyme that in humans is encoded by the LATS2 gene.
Serine/threonine-protein kinase 13 is an enzyme that in humans is encoded by the AURKC gene.
Serine/threonine-protein kinase PLK4 also known as polo-like kinase 4 is an enzyme that in humans is encoded by the PLK4 gene. The Drosophila homolog is SAK, the C elegans homolog is zyg-1, and the Xenopus homolog is Plx4.
Serine/threonine-protein kinase 10 is an enzyme that in humans is encoded by the STK10 gene.
Volasertib is an experimental small molecule inhibitor of the PLK1 protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.
BI 811283 is a small molecule inhibitor of the Aurora B kinase protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. BI 811283 is currently in the early stages of clinical development and is undergoing first in human trials in patients with solid tumors and acute myeloid leukemia.
