Structural insight into human CK2α in complex with the potent inhibitor ellagic acid

Urolithin as a Converging Scaffold Linking Ellagic acid and Coumarin Analogues: Design of Potent Protein Kinase CK2 Inhibitors

“…On the other side, the hydroxy groups at positions 3 and 2 interact with the side chains of Lys 68 and Asp 175, respectively. [18] Furthermore, the hydroxy group at position 7 of the coumarin moiety has already been described as an essential feature for activity, even though it alone is not sufficient to achieve an IC 50 value in the sub-micromolar range. [19] Indeed, to increase the inhibitory potency, an electron-withdrawing substituent should be simultaneously present at position 8.…”

“…[18,19] Like all known inhibitors of CK2, where the a-subunit crystal structure is available, both ellagic acid and DBC bind inside the ATP binding cleft of the catalytic domain of CK2, and they can be classified as type I or ATP-competitive inhibitors.…”

“…[19] However, while DBC does not bind the hinge region directly, ellagic acid interacts both with the hinge region and the ATP phosphate group binding area, as deduced by the three-dimensional crystallographic complex recently reported. [18] The hydroxy group at position 7 of ellagic acid interacts with the carboxyl oxygen of the hinge-region residue Glu 114 through a water bridge (W2), while the hydroxy group in position 8 binds a nearby water molecule (W3) connected to Asn 118 and a carboxyl oxygen of Val 116 in the hinge region. On the other side, the hydroxy groups at positions 3 and 2 interact with the side chains of Lys 68 and Asp 175, respectively.…”

“…To explore the potential oncological applications of the more promising novel CK2 inhibitors, the cytotoxicity profile of to the active site of human CK2 (PDB: 2ZJW [18] ).…”

“…[18,19] The availability of structural information is generally accepted to be a requirement for the Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (K i = 20 nm) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, K i = 60 nm).…”