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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.

Contents

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

References

  1. ^ 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
  2. ^ 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
  3. ^ 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
  4. ^ Nigg E.A. Mitotic kinases as regulators of cell division and its checkpoints Nat. Rev. Mol. Cell Biol. 2:21-32 (2001)
  5. ^ Nicholas Keen & Stephen Taylor, Aurora-kinase inhibitors as anticancer agents. Nature Reviews Cancer 4, 927-36 (2004)
  6. ^ Richard D. Carvajal, Archie Tse, and Gary K. Schwartz Aurora Kinases: New Targets for Cancer Therapy Clin. Cancer Res., (2006) 12: pp.6869-75.
  7. ^ 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
  8. ^ 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
  9. ^ Edmund Chun Yu Lee et al., Targeting Aurora Kinases for the Treatment of Prostate Cancer. Cancer Res. (2006) 66: pp.4996-5002.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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
  14. ^ Shiho Sakita-Suto et al., Aurora-B Regulates RNA Methyltransferase NSUN2 Mol. Biol. Cell, (2007) 18: pp.1107 17
  15. ^ 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)
  16. ^ 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
  17. ^ Graham M. T. et al., Crystal Structure of Aurora-2, an Oncogenic Serine/Threonine Kinase J. Biol. Chem., (2002) 277: pp.42419-22
v • d • e
Kinases: Serine/threonine-specific protein kinases (primarily EC 2.7.11)
2.7.11Pyruvate dehydrogenase kinase - Protein kinase A - Protein kinase G - Protein kinase C (Protein kinase Mζ) - Rhodopsin - Beta adrenergic receptor - G-protein coupled receptor kinases - Ca2+/calmodulin-dependent - Myosin light-chain) - Phosphorylase - Cyclin-dependent - Mitogen-activated (Extracellular signal-regulated, C-Jun N-terminal (MAPK8, MAPK9), P38 mitogen-activated protein) - MAP3K - GSK-3 - AMP-activated
2.7.12MAP2K
2.7.1.37, or unknownAnti-Mullerian hormone receptor - Ataxia telangiectasia mutated - Aurora (A, B) - Mammalian target of rapamycin - Bone morphogenetic protein receptors (1, 2) - CDKL5 - c-Raf - EIF-2 - Ribosomal s6 - Protein kinase B - PDK1
v • d • e
Phosphotransferases/kinases (EC 2.7)
2.7.1 - OH acceptorHexo- - 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 acceptorPhosphoglycerate - Aspartate
2.7.3 - N acceptorCreatine
2.7.4 - PO4 acceptorPhosphomevalonate - Adenylate - Nucleoside-diphosphate
2.7.6 - P2O7Ribose-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 - proteinTyrosine - Serine/threonine-specific
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Aurora_inhibitors". A list of authors is available in Wikipedia.
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