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CK2 Inhibition

The oncogenic potential of CK2 and its involvement in virally mediated pathologies has led to an increasing number of studies aimed at the discovery of selective inhibitors. These molecules could constitute not only lead compounds for drug development, but also useful tools for the clarification of the protein function in vivo.

An important aspect of CK2 that could simplify the drug design process is that this enzyme is always active and does not undergo the relevant con-formational changes typical of most protein kinases. This circumstance allows us to overcome the difficulty that sometimes arises in correlating biochemical inhibition data, often obtained with activated kinases, with structural data derived from inhibitors bound to the inactive form of the enzyme. Moreover, it is not always possible to crystallize protein kinases in their active state. In the case of complexes with the inactive form of kinases, caution must be used in the straightforward interpretation of the inhibition data in terms of structural details that can represent a situation slightly but significantly different from that occurring in the biochemical experiments. However, there are examples, as with the Abl kinase, where the structure of the complex between an inhibitor, Gleevec in this case, bound to an inactive state of the enzyme could help in the interpretation of the biochemical data.

Two characteristics of CK2 must be considered in the development of highly specific inhibitors: (a) the active site can utilize both ATP and GTP as co-substrates and this feature is quite unique among kinases that usually are specific for ATP; (b) staurosporine is a well-known, potent inhibitor of protein kinases, with a really broad spectrum of activity, but it is only marginally efficient on CK2 (Meggio et al. 1995). These two features indicate that the catalytic site of CK2 has some unique characteristics that can be exploited to design inhibitors with a high degree of specificity. The determination of the three-dimensional structure of CK2 in complex with different inhibitors is an essential step in the elucidation of the critical properties of the active site.

In recent years we have determined the crystal structure of several complexes between the a-catalytic subunit of CK2 from Zea mays and ATP site-directed inhibitors. In particular, we have studied four members of the an-thraquinone-related compounds, one halogenated benzotriazole and an in-doloquinazolinone derivative.

To date, the best-characterized classes of CK2 inhibitor are the following: (a) hydroxylated polycyclic aromatic compounds with anthraquinone/xan-thenone or fluorenone or flavone scaffolds; (b) halogenated benzimidazoles or benzotriazoles; (c) indole derivatives of quinazolinone.

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