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

• DOI: 10.1002/cmdc.201100338
• Publication Date: 2011-10-04T08:35:17Z
• Authors: Giorgio Cozza; Alessandra Gianon...; Paolo Bonvini; Elisa Zorzi; Riccardo Pasquale; Angelo Rosolen; Lorenzo A. Pinna; Flavio Meggio; Giuseppe Zagotto; Stefano Moro
• Keywords: Ellagic Acid

Abstract Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity suspected to underlie pathogenic potential in neoplasia other relevant diseases. Previously, using different silico screening approaches, two potent selective CK2 inhibitors were identified by our group: ellagic acid, naturally occurring tannic acid derivative ( K i =20 n M ) 3,8‐dibromo‐7‐hydroxy‐4‐methylchromen‐2‐one (DBC, =60 ). Comparing the crystallographic binding modes of both DBC, an X‐ray structure‐driven merging approach was taken design novel with improved target affinity. A urolithin moiety proposed as possible bridging scaffold between known inhibitors, DBC. Optimization led identification 4‐bromo‐3,8‐dihydroxy‐benzo[c]chromen‐6‐one novel, inhibitor, which shows value 7 against kinase, representing significant improvement affinity for compared parent fragments.