title: Inspecting the structure-activity relationship of protein kinase CK2 inhibitors derived from tetrabromo-benzimidazole.
abstract: CK2 is a very pleiotropic protein kinase whose high constitutive activity is suspected to cooperate to neoplasia. Here, the crystal structure of the complexes between CK2 and three selective tetrabromo-benzimidazole derivatives inhibiting CK2 with Ki values between 40 and 400 nM are presented. The ligands bind to the CK2 active site in a different way with respect to the parent compound TBB. They enter more deeply into the cavity, establishing halogen bonds with the backbone of Glu114 and Val116 in the hinge region. A detailed analysis of the interactions highlights a major role of the hydrophobic effect in establishing the rank of potency within this class of inhibitors and shows that polar interactions are responsible for the different orientation of the molecules in the active site.
authors.affiliation: Department of Chemistry, University of Padua, via Marzolo 1, 35131 Padua, Italy. roberto.battistutta@unipd.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Battistutta
authors.forename: Marco
authors.initials: M
authors.lastname: Mazzorana
authors.forename: Stefania
authors.initials: S
authors.lastname: Sarno
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Kazimierczuk
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanotti
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D001966:Bromine / Q000737:chemistry*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C475924:4,5,6,7-tetrabromobenzimidazole; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C031000:benzimidazole; D047390:Casein Kinase II; D001966:Bromine