Aurora inhibitors

Aurora kinases regulate cell cycle transit from G2 through cytokinesis and, thus, are targets in cancer therapy [Andrews PD, Knatko E, Moore WJ, Swedlow JR. Mitotic mechanics: the auroras come into view. Current Opin in Cell Biol.(2003) 15: pp.672-83] . 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 [Katayama H., Brinkley WR, Sen S. The Aurora kinases: Role in cell transformation and tumorigenesis. "Cancer and Metastasis Reviews" (2003) 22(4): pp.451-64] with aurora A identified as a low penetrance tumor susceptibility gene in mice and humans [Ewart-Toland A, Briassoului P, de Koning JP et al, Identification of Stk6/STK15 as a candidate low-penetrance tumor susceptibility gene in mouse and human. "Nature Genetics" (2003) 34(4): pp.403-12] . Aurora kinases could be potential targets for novel small-molecule enzyme inhibitors.

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 [Nigg E.A. Mitotic kinases as regulators of cell division and its checkpoints "Nat. Rev. Mol. Cell Biol." 2:21-32 (2001)] . 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 [Nicholas Keen & Stephen Taylor, Aurora-kinase inhibitors as anticancer agents. "Nature Reviews Cancer" 4, 927-36 (2004)] [Richard D. Carvajal, Archie Tse, and Gary K. Schwartz Aurora Kinases: New Targets for Cancer Therapy Clin. Cancer Res., (2006) 12: pp.6869-75.] . The Aurora enzymes are particularly exciting because they are involved in a direct path to the nucleosome by phosphorylating histone H3 [H Goto, Y Yasui, EA Nigg, and M Inagaki Aurora-B phosphorylates Histone H3 at serine28 with regard to the mitotic chromosome condensation Genes Cells, (2002) 7: pp11-7] [Karine Monier, Sandrine Mouradian, and Kevin F. Sullivan DNA methylation promotes Aurora-B-driven phosphorylation of histone H3 in chromosomal subdomain J. Cell Sci., (2007) 120: pp.101-14] . Furthermore, Aurora kinases are known to be oncogenic and overexpressed in various forms of cancerous growth, including leukemia, colon cancer, prostate cancer [Edmund Chun Yu Lee et al., Targeting Aurora Kinases for the Treatment of Prostate Cancer. "Cancer Res." (2006) 66: pp.4996-5002.] and breast cancer [Hua Yang et al., Aurora-A Kinase Regulates Telomerase Activity through c-Myc in Human Ovarian and Breast Epithelial Cells "Cancer Res". (2004) 64: pp.463-67.] tumors [Jingyan Fu, Minglei Bian, Qing Jiang, and Chuanmao Zhang Roles of Aurora Kinases in Mitosis and Tumorigenesis Mol. Cancer Res., (2007) 5: pp.1-10.] . So far three Aurora-kinase inhibitors have been described: ZM447439 [Bedrick B. Gadea and Joan V. Ruderman Aurora Kinase Inhibitor ZM447439 Blocks Chromosome-induced Spindle Assembly, the Completion of Chromosome Condensation, and the Establishment of the Spindle Integrity Checkpoint in Xenopus Egg Extracts "Mol. Biol. Cell", (2005) 16: pp.1305-18.] , Hesperadin [Hauf, S. et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. "J. Cell Biol." (2003) 161, pp.281–94] [Shiho Sakita-Suto et al., Aurora-B Regulates RNA Methyltransferase NSUN2 "Mol. Biol. Cell", (2007) 18: pp.1107 17] 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. [Harrington, E. A. et al. VX-680, a potent and selective small molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. "Nature Med." 10, 262–7 (2004)] , although the Phase II clinical trial was suspended in November, 2007 due to QT prolongation observed in one patient in Phase I trial.

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 [Donehower RC and Rowinsky EK (1993) Anticancer drugs derived from plants, in Cancer: Principles and Practice of Oncology (De Vita VT, Hellman S, and Rosenberg SA editors) pp 409–417, Lippincott, Philadelphia] .

Aurora structure

The structure and active site of Aurora-2-adenosine complex has been determined [Graham M. T. et al., Crystal Structure of Aurora-2, an Oncogenic Serine/Threonine Kinase J. Biol. Chem., (2002) 277: pp.42419-22] . 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.

ee also

* Kinome
* Cyclin-dependent kinase
* Signal transduction

References

External links

* [http://ca.expasy.org/uniprot/O14965 Aurora-A (Serine/threonine-protein kinase 6, AIK, ARK1, AURA, BTAK, STK15, STK6)]
* [http://ca.expasy.org/uniprot/Q96GD4 Aurora-B (Serine/threonine-protein kinase 12, AIK2, AIM1, ARK2, STK12)]
* [http://ca.expasy.org/uniprot/Q9UQB9 Aurora-C (Serine/threonine-protein kinase 13, AIE2, AIK3, STK13)]