3-hydroxy-4'-carboxyflavone derivatives (FLC)

With the aim to identify new CK2 inhibitors virtual screening of 150,000 small organic compounds has been performed. As a result, were have found and tested in vitro 13 carboxyl-containing flavone derivatives able to inhibit protein kinase activity (IC₅₀ < 10 μM). Studying structure–activity relationships of these novel CK2 inhibitors, we analyzed their docking complexes and developed a binding model of the flavone derivatives in CK2 ATP-binding site. From these considerations, extra 13 derivatives of 3-hydroxy-4’-carboxyflavone were synthesized and tested in vitro toward CK2.

Kinetic studies of one of the most active flavonol derivative, FLC21 – 4-(6,8 Dichloro-3-hydroxy-4-oxo-chroman-2-yl)-benzoic acid (IC₅₀ = 40 nM) showed competitive mode of inhibitory action. The corresponding K_i value is 13 nM. Evaluation of the inhibitors on seven protein kinases revealed considerable selectivity towards CK2. With the aid of combinatorial organic synthesis, molecular modelling techniques and biochemical in vitro tests, we studied the structure–activity relationships of new flavonol derivatives and developed binding model describing their key intermolecular interactions with the CK2 ATP-binding site.

Figure 1. The binding mode of FLC21 in the CK2 active site. Hydrogen bonds are shown by the dotted lines.

The represented structural and biological data along with the developed binding model could be used for further optimization of this class of compounds as a potent inhibitors of human CK2 and/or other protein kinases.

• Structure-based discovery of novel flavonol inhibitors of human protein kinase CK2. Golub AG, Bdzhola VG, Kyshenia YV, Sapelkin VM, Prykhod'ko AO, Kukharenko OP, Kotey IM, Ostrynska OV, Yarmoluk SM. Mol Cell Biochem. 2011, 356 (1-2): 107-115.