title: Discovery of a potent and selective protein kinase CK2 inhibitor by high-throughput docking.
abstract: To assess the potential of protein kinase CK2 as a target for developing new antitumor agents, we have undertaken a search for inhibitors of this enzyme. As part of this effort, we report here the discovery of the potent and selective CK2 inhibitor (5-oxo-5,6-dihydroindolo[1,2-a]quinazolin-7-yl)acetic acid. We identified this inhibitor of a novel structural type by high-throughput docking of our corporate compound collection in the ATP binding site of a homology model of human CK2, using an appropriate protocol. The synthesis of the inhibitor as well as that of related analogues whose CK2 inhibitory activities give support to the binding mode proposed by the docking program is described. The results obtained suggest that virtual screening of a 3D database by molecular docking is a useful approach for lead finding provided that adapted postdocking filtering and reranking procedures are applied to the primary hit list.
authors.affiliation: Oncology Research, Novartis Pharma AG, 4002 Basle, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.forename: Kaspar
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoepfer
authors.forename: Robert
authors.initials: R
authors.lastname: Portmann
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D047390:Casein Kinase II; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D003313:Zea mays / Q000737:chemistry
chemical_list: C475515:(5-oxo-5,6-dihydroindolo(1,2-a)quinazolin-7-yl)acetic acid; D000085:Acetates; D004791:Enzyme Inhibitors; D011799:Quinazolines; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases