Aurora kinase inhibitors are a putative drug class for treating cancer. The Aurora kinase enzymes could be potential targets for novel small-molecule enzyme inhibitors.
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]
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 nucleosomebyphosphorylating 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]
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| 2.7.1-2.7.4: phosphotransferase/kinase (PO4) |
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| 2.7.6: diphosphotransferase (P2O7) |
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| 2.7.7: nucleotidyltransferase (PO4-nucleoside) |
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| 2.7.8: miscellaneous |
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| 2.7.10-2.7.13: protein kinase (PO4; protein acceptor) |
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