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Indoloquinazolinones

To identify new inhibitors, a virtual screening analysis among the in-house collection of chemical compounds has recently been performed by researchers of Novartis Pharma against a human CK2 three-dimensional model (Vangrevelinghe et al. 2003). This analysis has led to the discovery of a new class of potent and selective inhibitors of CK2, the indoloquinazolinones. The most promising compound, IQA [(5-oxo-5,6-dihydro-indolo(1,2-a)quinazolin-7-yl)acetic acid], with a Ki of 0.17 mM, has been co-crystallized in complex with CK2 (Table 1) and the final three-dimensional structure at 1.68 A resolution has been recently reported (Sarno et al. 2003).

IQA lays inside the catalytic pocket of CK2 on the same plane occupied by the ATP purine moiety. The hydrophobic side of IQA faces the hinge region of the protein, while the polar side is oriented toward Lys68. IQA is found in the ATP-binding site in two different orientations, differing for a rotation of the acetate function (Fig. 13). The two alternative conformations have been refined with final occupancies of 50%. In the first conformation, the carboxylic function makes an internal hydrogen bond with the lactam nitrogen, closing a six-member ring, and interacts with the hydroxyl oxygen of Ser51. This conformation is largely favored in solution (Fig. 14), as confirmed by nuclear magnetic resonance (NMR) spectroscopy analysis. Therefore, it has to be assumed that the second conformation is stabilized when bound to the CK2 active site, where it is found as abundant as the first one. In fact, in the second conformation the carboxylate group is involved in

Fig. 13A, B Polar interactions of IQA with Ser51, Lys68, and Asp175 of CK2. IQA binds to CK2 in two conformations, shown in A and B

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