title: Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2.
abstract: Structurally diverse inhibitors of the protein kinase CK2 are required for regulation of this ubiquitous protein to establish biological roles of the enzyme which catalyzes the phosphorylation of a vast number of substrate proteins. In this article we disclose a series of new bisubstrate inhibitors of CK2 that are structurally represented by the oligo(l-Asp) peptide conjugates of benzo[c][2,6]naphthyridine-8-carboxylic acid. This fragment originated from CX-4945, the first in class inhibitor taken to clinical trials. The most potent conjugates possessed two-digit picomolar affinity and clear selectivity for CK2α in a panel of 140 protein kinases. Labeling of the inhibitors with a fluorescent dye yielded probes for a fluorescence anisotropy-based binding/displacement assay which can be used for analysis of CK2 and precise determination of affinity of the highly potent (tight-binding) CK2-targeting inhibitors.
authors.affiliation: Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Vahter
authors.affiliation: Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia.
authors.forename: Kaido
authors.initials: K
authors.lastname: Viht
authors.affiliation: Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia.
authors.forename: Asko
authors.initials: A
authors.lastname: Uri
authors.affiliation: Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia. Electronic address: Erki.Enkvist@ut.ee.
authors.forename: Erki
authors.initials: E
authors.lastname: Enkvist
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D001224:Aspartic Acid; D047390:Casein Kinase II
keywords: Biligand; Bisubstrate inhibitor; CK2; Fluorescence anisotropy; Fluorescence probe; Protein kinase