Aurora inhibitor

In today's world, Aurora inhibitor is a topic that generates great interest and discussion in different areas. With the advancement of technology and globalization, Aurora inhibitor has become a fundamental aspect that impacts people's daily lives, both personally and professionally. From its origins to its relevance today, Aurora inhibitor has been the subject of study and analysis by experts in various fields, generating a wide range of opinions and perspectives. In this article, we will explore different aspects related to Aurora inhibitor, from its social implications to its influence on the global economy, with the aim of offering a comprehensive and enriching vision of this topic that is so relevant today.

Aurora case study – six inhibitors and their action during cytokinesis

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

Aurora's active center

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.[citation needed]

See also

References

  1. ^ Andrews, Paul D.; Knatko, Elena; Moore, William J.; Swedlow, Jason R. (2003). "Mitotic mechanics: The auroras come into view". Current Opinion in Cell Biology. 15 (6): 672–683. doi:10.1016/j.ceb.2003.10.013. PMID 14644191.
  2. ^ Katayama, Hiroshi; Brinkley, W. R.; Sen, S. (2003). "The Aurora kinases: Role in cell transformation and tumorigenesis". Cancer and Metastasis Reviews. 22 (4): 451–464. doi:10.1023/a:1023789416385. PMID 12884918. S2CID 25350728.
  3. ^ 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 (2003). "Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human". Nature Genetics. 34 (4): 403–412. doi:10.1038/ng1220. PMID 12881723. S2CID 29442841.
  4. ^ Nigg, Erich A. (2001). "Mitotic kinases as regulators of cell division and its checkpoints". Nature Reviews Molecular Cell Biology. 2 (1): 21–32. doi:10.1038/35048096. PMID 11413462. S2CID 205011994.
  5. ^ Keen, Nicholas; Taylor, Stephen (2004). "Aurora-kinase inhibitors as anticancer agents". Nature Reviews Cancer. 4 (12): 927–936. doi:10.1038/nrc1502. PMID 15573114. S2CID 28256419.
  6. ^ Carvajal, R. D.; Tse, A.; Schwartz, G. K. (2006). "Aurora Kinases: New Targets for Cancer Therapy". Clinical Cancer Research. 12 (23): 6869–6875. doi:10.1158/1078-0432.CCR-06-1405. PMID 17145803. S2CID 34256297.
  7. ^ Goto, Hidemasa; Yasui, Yoshihiro; Nigg, Erich A.; Inagaki, Masaki (2002). "Aurora-B phosphorylates Histone H3 at serine28 with regard to the mitotic chromosome condensation". Genes to Cells. 7 (1): 11–17. doi:10.1046/j.1356-9597.2001.00498.x. PMID 11856369.
  8. ^ Monier, K.; Mouradian, S.; Sullivan, K. F. (2006). "DNA methylation promotes Aurora-B-driven phosphorylation of histone H3 in chromosomal subdomains". Journal of Cell Science. 120 (Pt 1): 101–114. doi:10.1242/jcs.03326. PMID 17164288. S2CID 30767479.
  9. ^ Lee, Edmund Chun Yu; Frolov, Anna; Li, Rile; Ayala, Gustavo; Greenberg, Norman M. (2006). "Targeting Aurora Kinases for the Treatment of Prostate Cancer". Cancer Research. 66 (10): 4996–5002. doi:10.1158/0008-5472.CAN-05-2796. PMID 16707419.
  10. ^ Yang, Hua; Ou, Chien Chen; Feldman, Richard I.; Nicosia, Santo V.; Kruk, Patricia A.; Cheng, Jin Q. (2004). "Aurora-A Kinase Regulates Telomerase Activity through c-Myc in Human Ovarian and Breast Epithelial Cells". Cancer Research. 64 (2): 463–467. doi:10.1158/0008-5472.can-03-2907. PMID 14744757. S2CID 11727346.
  11. ^ Fu, J.; Bian, M.; Jiang, Q.; Zhang, C. (2007). "Roles of Aurora Kinases in Mitosis and Tumorigenesis". Molecular Cancer Research. 5 (1): 1–10. doi:10.1158/1541-7786.MCR-06-0208. PMID 17259342. S2CID 22233833.
  12. ^ Gadea, Bedrick B.; Ruderman, Joan V. (2005). "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". Molecular Biology of the Cell. 16 (3): 1305–1318. doi:10.1091/mbc.e04-10-0891. PMC 551494. PMID 15616188.
  13. ^ Peters, Jan-Michael; Rieder, Conly L.; Van Meel, Jacques; Heckel, Armin; Walter, Rainer; Schnapp, Gisela; Zimmer, Christine; Laterra, Sabrina; Cole, Richard W.; Hauf, Silke (2003). "The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint". Journal of Cell Biology. 161 (2): 281–294. doi:10.1083/jcb.200208092. PMC 2172906. PMID 12707311.
  14. ^ Sakita-Suto, Shiho; Kanda, Akifumi; Suzuki, Fumio; Sato, Sunao; Takata, Takashi; Tatsuka, Masaaki (2007). "Aurora-B Regulates RNA Methyltransferase NSUN2". Molecular Biology of the Cell. 18 (3): 1107–1117. doi:10.1091/mbc.e06-11-1021. PMC 1805108. PMID 17215513.
  15. ^ 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. (2004). "VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo". Nature Medicine. 10 (3): 262–267. doi:10.1038/nm1003. PMID 14981513. S2CID 12918452.
  16. ^ Graham M. T. et al., Crystal Structure of Aurora-2, an Oncogenic Serine/Threonine Kinase J. Biol. Chem., (2002) 277: pp.42419-22