title: Acetoxymethyl Ester of Tetrabromobenzimidazole-Peptoid Conjugate for Inhibition of Protein Kinase CK2 in Living Cells.
abstract: CK2 is a ubiquitous serine/threonine protein kinase, which has the potential to catalyze the generation of a large proportion of the human phosphoproteome. Due to its role in numerous cellular functions and general anti-apoptotic activity, CK2 is an important target of research with therapeutic potential. This emphasizes the need for cell-permeable highly potent and selective inhibitors and photoluminescence probes of CK2 for investigating the protein phosphorylation networks in living cells. Previously, we had developed bisubstrate inhibitors for CK2 (CK2-targeted ARCs) that showed remarkable affinity (KD < 1 nM) and selectivity, but lacked proteolytic stability and plasma membrane permeability. In this report, the structures of CK2-targeted ARCs were modified for the application in live cells. Based on structure-activity studies, proteolytically stable achiral oligoanionic peptoid conjugates of 4,5,6,7-tetrabromo-1H-benzimidazole (TBBz) were constructed. Affinity of the conjugates toward CK2 reached subnanomolar range. Acetoxymethyl (AM) prodrug strategy was applied for loading TBBz-peptoid conjugates into living cells. The uptake of inhibitors was visualized by live cell imaging and the reduction of the phosphorylation levels of two CK2-related phosphosites, Cdc37 pSer13 and NFκB pSer529, was demonstrated by Western blot analysis.
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Kaido
authors.initials: K
authors.lastname: Viht
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Siiri
authors.initials: S
authors.lastname: Saaver
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Vahter
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Erki
authors.initials: E
authors.lastname: Enkvist
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Darja
authors.initials: D
authors.lastname: Lavogina
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Hedi
authors.initials: H
authors.lastname: Sinijärv
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Gerda
authors.initials: G
authors.lastname: Raidaru
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark , Campusvej 55, DK-5230 Odense, Denmark.
authors.forename: Barbara
authors.initials: B
authors.lastname: Guerra
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark , Campusvej 55, DK-5230 Odense, Denmark.|KinaseDetect Aps , Skovvej 22, 6340 Kruså, Denmark.
authors.forename: Olaf-Georg
authors.initials: OG
authors.lastname: Issinger
authors.affiliation: Institute of Chemistry, University of Tartu , Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Asko
authors.initials: A
authors.lastname: Uri
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004951:Esterification; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D034444:Peptoids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C475924:4,5,6,7-tetrabromobenzimidazole; D001562:Benzimidazoles; D034444:Peptoids; D047428:Protein Kinase Inhibitors; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II