Aurora kinases regulate cell cycle transit from G2 through cytokinesis and, thus, are targets in cancer therapy. 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 with aurora A identified as a low penetrance tumor susceptibility gene in mice and humans. Aurora kinases could be potential targets for novel small-molecule enzyme inhibitors.
Additional recommended knowledge
A new approach to inhibiting cancer growth that shows great promise for structure-based drug development is targeting enzymes central to cellular mitosis. 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. The Aurora enzymes are particularly exciting because they are involved in a direct path to the nucleosome by phosphorylating histone H3. Furthermore, Aurora kinases are known to be oncogenic and overexpressed in various forms of cancerous growth, including leukemia, colon cancer, prostate cancer and breast cancer tumors. So far three Aurora-kinase inhibitors have been described: ZM447439, Hesperadin 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..
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.
The structure and active site of Aurora-2-adenosine complex has been determined. 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.
- ^ 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
- ^ 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
- ^ 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
- ^ Nigg E.A. Mitotic kinases as regulators of cell division and its checkpoints Nat. Rev. Mol. Cell Biol. 2:21-32 (2001)
- ^ 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.
- ^ 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
- ^ Edmund Chun Yu Lee et al., Targeting Aurora Kinases for the Treatment of Prostate Cancer. Cancer Res. (2006) 66: pp.4996-5002.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
- ^ 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)
- ^ 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, JB Lippincott, Philadelphia
- ^ Graham M. T. et al., Crystal Structure of Aurora-2, an Oncogenic Serine/Threonine Kinase J. Biol. Chem., (2002) 277: pp.42419-22
|Phosphotransferases/kinases (EC 2.7)|
|2.7.1 - OH acceptor||Hexo- - Gluco- - Fructo- (Hepatic fructo-) - Galacto- - Phosphofructo- (1, 2) - Thymidine - NAD+ - Glycerol - Pantothenate - Mevalonate - Pyruvate - Deoxycytidine - PFP - Diacylglycerol - Bruton's tyrosine - Phosphoinositide 3 (Class I PI 3, Class II PI 3) - Sphingosine|
|2.7.2 - COOH acceptor||Phosphoglycerate - Aspartate|
|2.7.3 - N acceptor||Creatine|
|2.7.4 - PO4 acceptor||Phosphomevalonate - Adenylate - Nucleoside-diphosphate|
|2.7.6 - P2O7||Ribose-phosphate diphosphokinase - Thiamine pyrophosphokinase|
|2.7.7 - nucleotidyl-||Integrase - PNPase - Polymerase - RNase PH - UDP-glucose pyrophosphorylase - Galactose-1-phosphate uridylyltransferase -Terminal deoxynucleotidyl transferase - RNA replicase - Reverse transcriptase (Telomerase) - Transposase|
|2.7.8 - other phos.||N-acetylglucosamine-1-phosphate transferase|
|2.7.10-11 - protein||Tyrosine - Serine/threonine-specific|