Aurora inhibitor explained

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]

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 significant 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] although the Phase II clinical trial was suspended in November, 2007 due to QT prolongation observed in one patient in Phase I trial.

Aurora structure

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.

See also

External links

Notes and References

  1. 10.1016/j.ceb.2003.10.013. Mitotic mechanics: The auroras come into view. 2003. Andrews. Paul D.. Knatko. Elena. Moore. William J.. Swedlow. Jason R.. Current Opinion in Cell Biology. 15. 6. 672–683. 14644191.
  2. 10.1023/a:1023789416385. 2003. Katayama. Hiroshi. Brinkley. W. R.. Sen. S.. 25350728. The Aurora kinases: Role in cell transformation and tumorigenesis. Cancer and Metastasis Reviews. 22. 4. 451–464. 12884918.
  3. 10.1038/ng1220. Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. 2003. Ewart-Toland. Amanda. Briassouli. Paraskevi. De Koning. John P.. Mao. Jian-Hua. Yuan. Jinwei. Chan. Florence. Maccarthy-Morrogh. Lucy. Ponder. Bruce A J.. Nagase. Hiroki. Burn. John. Ball. Sarah. Almeida. Maria. Linardopoulos. Spiros. Balmain. Allan. 29442841. Nature Genetics. 34. 4. 403–412. 12881723.
  4. 10.1038/35048096. Mitotic kinases as regulators of cell division and its checkpoints. 2001. Nigg. Erich A.. 205011994. Nature Reviews Molecular Cell Biology. 2. 1. 21–32. 11413462.
  5. 10.1038/nrc1502. Aurora-kinase inhibitors as anticancer agents. 2004. Keen. Nicholas. Taylor. Stephen. 28256419. Nature Reviews Cancer. 4. 12. 927–936. 15573114.
  6. 10.1158/1078-0432.CCR-06-1405. Aurora Kinases: New Targets for Cancer Therapy. 2006. Carvajal. R. D.. Tse. A.. Schwartz. G. K.. 34256297. Clinical Cancer Research. 12. 23. 6869–6875. 17145803. free.
  7. 10.1046/j.1356-9597.2001.00498.x. Aurora-B phosphorylates Histone H3 at serine28 with regard to the mitotic chromosome condensation. 2002. Goto. Hidemasa. Yasui. Yoshihiro. Nigg. Erich A.. Inagaki. Masaki. Genes to Cells. 7. 1. 11–17. 11856369.
  8. 10.1242/jcs.03326. DNA methylation promotes Aurora-B-driven phosphorylation of histone H3 in chromosomal subdomains. 2006. Monier. K.. Mouradian. S.. Sullivan. K. F.. 30767479. Journal of Cell Science. 120. Pt 1. 101–114. 17164288. free.
  9. 10.1158/0008-5472.CAN-05-2796. Targeting Aurora Kinases for the Treatment of Prostate Cancer. 2006. Lee. Edmund Chun Yu. Frolov. Anna. Li. Rile. Ayala. Gustavo. Greenberg. Norman M.. Cancer Research. 66. 10. 4996–5002. 16707419. free.
  10. 10.1158/0008-5472.can-03-2907. Aurora-A Kinase Regulates Telomerase Activity through c-Myc in Human Ovarian and Breast Epithelial Cells. 2004. Yang. Hua. Ou. Chien Chen. Feldman. Richard I.. Nicosia. Santo V.. Kruk. Patricia A.. Cheng. Jin Q.. 11727346. Cancer Research. 64. 2. 463–467. 14744757. free.
  11. 10.1158/1541-7786.MCR-06-0208. Roles of Aurora Kinases in Mitosis and Tumorigenesis. 2007. Fu. J.. Bian. M.. Jiang. Q.. Zhang. C.. 22233833. Molecular Cancer Research. 5. 1. 1–10. 17259342. free.
  12. 10.1091/mbc.e04-10-0891. Aurora Kinase Inhibitor ZM447439 Blocks Chromosome-induced Spindle Assembly, the Completion of Chromosome Condensation, and the Establishment of the Spindle Integrity Checkpoint inXenopus Egg Extracts. 2005. Gadea. Bedrick B.. Ruderman. Joan V.. Molecular Biology of the Cell. 16. 3. 1305–1318. 15616188. 551494.
  13. 10.1083/jcb.200208092. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint. 2003. Peters. Jan-Michael. Rieder. Conly L.. Van Meel. Jacques. Heckel. Armin. Walter. Rainer. Schnapp. Gisela. Zimmer. Christine. Laterra. Sabrina. Cole. Richard W.. Hauf. Silke. Journal of Cell Biology. 161. 2. 281–294. 12707311. 2172906.
  14. 10.1091/mbc.e06-11-1021. Aurora-B Regulates RNA Methyltransferase NSUN2. 2007. Sakita-Suto. Shiho. Kanda. Akifumi. Suzuki. Fumio. Sato. Sunao. Takata. Takashi. Tatsuka. Masaaki. Molecular Biology of the Cell. 18. 3. 1107–1117. 17215513. 1805108.
  15. 10.1038/nm1003. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. 2004. Harrington. Elizabeth A.. Bebbington. David. Moore. Jeff. Rasmussen. Richele K.. Ajose-Adeogun. Abi O.. Nakayama. Tomoko. Graham. Joanne A.. Demur. Cecile. Hercend. Thierry. Diu-Hercend. Anita. Su. Michael. Golec. Julian M C.. Miller. Karen M.. 12918452. Nature Medicine. 10. 3. 262–267. 14981513.
  16. Graham M. T. et al., Crystal Structure of Aurora-2, an Oncogenic Serine/Threonine Kinase J. Biol. Chem., (2002) 277: pp.42419-22

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