Prudent Renaud, Moucadel Virginie, Laudet Béatrice, Barette Caroline, Lafanechère Laurence, Hasenknopf Bernold, Li Joaquim, Bareyt Sébastian, Lacôte Emmanuel, Thorimbert Serge, Malacria Max, Gouzerh Pierre, Cochet Claude
Laboratoire de Transduction du Signal, Institut de Recherche en Technologies et Sciences pour le Vivant, CEA, 17 Rue des Martyrs 38054 Grenoble, France.
Chem Biol. 2008 Jul 21;15(7):683-92. doi: 10.1016/j.chembiol.2008.05.018.
Protein kinase CK2 is a multifunctional kinase of medical importance that is dysregulated in many cancers. In this study, polyoxometalates were identified as original CK2 inhibitors. P2Mo18O62 has the most potent activity. It inhibits the kinase in the nanomolar range by targeting key structural elements located outside the ATP- and peptide substrate-binding sites. Several polyoxometalate derivatives exhibit strong inhibitory efficiency, with IC50 values < or = 10 nM. Furthermore, these inorganic compounds show a striking specificity for CK2 when tested in a panel of 29 kinases. Therefore, polyoxometalates are effective CK2 inhibitors in terms of both efficiency and selectivity and represent nonclassical kinase inhibitors that interact with CK2 in a unique way. This binding mode may provide an exploitable mechanism for developing potent drugs with desirable properties, such as enhanced selectivity relative to ATP-mimetic inhibitors.
蛋白激酶CK2是一种具有医学重要性的多功能激酶，在许多癌症中表达失调。在本研究中，多金属氧酸盐被鉴定为新型CK2抑制剂。P2Mo18O62具有最强的活性。它通过靶向位于ATP和肽底物结合位点之外的关键结构元件，在纳摩尔范围内抑制该激酶。几种多金属氧酸盐衍生物表现出很强的抑制效率，IC50值≤10 nM。此外，当在一组29种激酶中进行测试时，这些无机化合物对CK2表现出显著的特异性。因此，多金属氧酸盐在效率和选择性方面都是有效的CK2抑制剂，代表了以独特方式与CK2相互作用的非经典激酶抑制剂。这种结合模式可能为开发具有理想特性的强效药物提供一种可利用的机制，例如相对于ATP模拟抑制剂具有更高的选择性。
