title: Urolithin as a converging scaffold linking ellagic acid and coumarin analogues: design of potent protein kinase CK2 inhibitors.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, University of Padova, Viale Giuseppe Colombo 3, 35131 Padova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cozza
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gianoncelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonvini
authors.forename: Elisa
authors.initials: E
authors.lastname: Zorzi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pasquale
authors.forename: Angelo
authors.initials: A
authors.lastname: Rosolen
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Flavio
authors.initials: F
authors.lastname: Meggio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018360:Crystallography, X-Ray; D015195:Drug Design; D004610:Ellagic Acid / Q000031:analogs & derivatives*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D003374:Coumarins; D047428:Protein Kinase Inhibitors; C026423:3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one; D004610:Ellagic Acid; C030123:coumarin; D047390:Casein Kinase II