Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • Aurora kinases were initially identified as protein kinases

    2024-04-10

    Aurora kinases were initially identified as protein kinases essential for error-free chromosome segregation during mitosis and meiosis. Aurora A appears to control premetaphase events, such as bipolar spindle assembly 3, 4, with Aurora B and C directing metaphase and postmetaphase events, including cytokinesis 5, 6. Aurora B and C were later found to be responsible for the massive mitotic phosphorylation of serine 10 in histone H3 in vivo7, 8. All three kinases show oncogenic properties and were found to be overexpressed in many different cancers 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24. Aurora A was the first member identified as one of the main protein kinases regulating cell proliferation. As soon as a strong link between Aurora A and cancer was found, most pharmaceutical companies started trying to develop Aurora A inhibitors to be used in treating cancer. Thus, here we focus only on Aurora A inhibitors.
    Aurora A Inhibitors There are currently many commercially available Aurora A inhibitors, with several involved in dozens of clinical trials. Three main Aurora A inhibitors are presented here and in Table 1.
    The Role of Aurora A in Carcinogenesis
    Should Aurora A Inhibitors Be Developed? The first inhibitors were discovered more than 12 years ago and, although some efficiently inhibited kinase activity in vitro, none have progressed beyond a Phase III clinical trial. Nevertheless, there are several reasons why the development of Aurora A Spironolactone sale inhibitors should continue. Most importantly, when used in association with certain chemotherapeutic agents, such as taxanes (microtubule stabilizers), the results achieved have been promising 44, 45, 46, 47. Furthermore, a new approach based on kinome-wide small interfering (si)RNA) screening followed by kinase inhibitors has also yielded promising results (Box 1). Briefly, this approach takes advantage of the fact that tumor Spironolactone sale are not normal but instead have diverged and adapted new signaling pathways to their advantage, adapting so that they can proliferate [48]. By doing so, some protein kinases become essential for the tumor, while remaining superfluous for the normal surrounding cells. Identifying these kinases and inhibiting them with low doses of inhibitors would be an efficient way to kill tumor cells without affecting normal ones. This approach has been successfully used in pancreatic cancers, opening new therapeutic possibilities 49, 50. Note that this approach is predicated on access to a toolbox containing specific inhibitors for each protein kinase, inhibitors that can be used as a drug in chemotherapy (including an Aurora A inhibitor) (Figure 3).
    Improving the Search for Aurora A Inhibitors
    To be catalytically active, Aurora A must be phosphorylated at T288 in the activation loop, a phosphorylation thought to be due to a trans autophosphorylation mechanism 53, 54. In this process, a binding partner activates a reaction wherein an Aurora A kinase molecule phosphorylates another Aurora A molecule at T288. Consequently, any in vivo antiphosphoantibody detection of T288 phosphorylation will indicate that Aurora A is active. However, the method has some drawbacks. For instance, T288 phosphorylation may not be exclusively due to autophosphorylation. In vitro, protein kinase A (PKA) can phosphorylate Aurora A at T288 located in a PKA consensus sequence: RRXTL [91]. However, it is unlikely that PKA phosphorylates T288 in vivo[92]. p21 protein (Cdc42/Rac)-activated kinase 1 (PAK-1) can also phosphorylate Aurora A on T288 in vivo when localized at the centrosomes [93]. In this particular case, the T288 phosphorylation state reflects either PKA or PAK-1 activity rather than that of Aurora A. Aurora A has another threonine residue next to T288, and phosphorylation of T287 also activates Aurora A; this epitope is not detected by antiphospho-T288. In addition, at least in vitro, Aurora A activity is suppressed when both T288 and T287 are phosphorylated [94]. Aurora A remains inactive if dephosphorylated on T288, indicating that T288 phosphorylation is the first requirement for an active Aurora A kinase. However, T288 phosphorylation does not necessarily indicate that Aurora A is active, because the protein kinase activity is modulated by several other phosphorylation events. For instance, the kinase activity of Aurora A phosphorylated on T288 is strongly enhanced in contact with nucleophosmin. This increase is due to an autophosphorylation event on Aurora A S89 [95]. By contrast, the activity of Aurora A, previously phosphorylated at T288, can also be downregulated by S342 phosphorylation 92, 96. Similar to T288, this serine is in a PKA consensus sequence, and it can also be phosphorylated by PAK-1 93, 97 (Figure 5). The S342 in human Aurora A is conserved in X. laevis at position 349. It has been reported that S349 phosphorylation in Xenopus could be triggered by priming Aurora A, phosphorylated on T295 (equivalent of human T288), through GSK3 phosphorylation of two amino acid residues, S290 and S291, upstream of S349 [98]. This priming event appears to trigger S342 autophosphorylation. However, these data have only been obtained so far in X. laevis.