Aurora 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]. Aurora kinases could be potential targets for novel small-molecule enzyme inhibitors.

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Drug development

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 exciting 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].

Vinca Alkaloids

Vinca alkaloids, including the natural products vincristine and vinblastine and the semisynthetic derivatives vindesine and vinorelbine, are antimitotic drugs that are widely used in cancer treatment^[16].

Aurora structure

The structure and active site of Aurora-2-adenosine complex has been determined^[17]. 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.

See also

• Kinome
• Cyclin-dependent kinase
• Signal transduction

References