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

作者：Cozza Giorgio; Gianoncelli Alessandra; Bonvini Paolo; Zorzi Elisa; Pasquale Riccardo; Rosolen Angelo; Pinna Lorenzo A; Meggio Flavio; Zagotto Giuseppe; Moro Stefano^*

来源：ChemMedChem, 2011, 6(12): 2273-2286.

DOI：10.1002/cmdc.201100338

• cancer
• drug design
• kinase inhibitors
• protein kinase CK2
• urolithin A

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). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithin A as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a K(i) value of 7 nm against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments.

• 出版日期2011-12-9