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 penetrancetumor 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 phosphorylatinghistone 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.
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]
↑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. PMID14644191.
↑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. PMID12884918. S2CID25350728.
↑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. PMID12881723. S2CID29442841.
↑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. PMID11413462. S2CID205011994.
↑Keen, Nicholas; Taylor, Stephen (2004). "Aurora-kinase inhibitors as anticancer agents". Nature Reviews Cancer. 4 (12): 927–936. doi:10.1038/nrc1502. PMID15573114. S2CID28256419.
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