Jürgen Vahter

University of Tartu

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Erki Enkvist

University of Tartu

Kaido Viht

University of Tartu

Asko Uri

University of Tartu

Siiri Saaver

University of Tartu

Olaf‐Georg Issinger

University of Southern Denmark

Gerda Raidaru

University of Tartu

Karsten Niefind

University of Cologne

N. Bischoff

Fraunhofer Institute for Production Systems and Design Technology

Hedi Sinijärv

University of Tartu

Darja Lavõgina

University of Tartu

Cooperative Institutions

University of Tartu

German Cancer Research Center

University of Cologne

University of Southern Denmark

Norwegian Institute of Bioeconomy Research

Stockholm University

Fischer (Germany)

Competence Centre on Health Technologies (Estonia)

École Polytechnique Fédérale de Lausanne

Universidade Federal do Rio de Janeiro

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Thiazole- and selenazole-comprising high-affinity inhibitors possess bright microsecond-scale photoluminescence in complex with protein kinase CK2

Bioorganic & Medicinal Chemistry (2018)

Jürgen Vahter Kaido Viht Asko Uri Ganesh babu Manoharan Erki Enkvist

Microsecond

10.1016/j.bmc.2018.09.003

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Citations (15)

Synthesis of high affinity inhibitors for protein kinase CK2

Jürgen Vahter

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Complex structure of human protein kinase CK2 catalytic subunit crystallized in the presence of a bisubstrate inhibitor

Erki Enkvist Kaido Viht N. Bischoff Jürgen Vahter Siiri Saaver

10.2210/pdb4fbx/pdb

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Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2

Bioorganic & Medicinal Chemistry (2017)

Jürgen Vahter Kaido Viht Asko Uri Erki Enkvist

Conjugate

10.1016/j.bmc.2017.02.055

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Acetoxymethyl Ester of Tetrabromobenzimidazole–Peptoid Conjugate for Inhibition of Protein Kinase CK2 in Living Cells

Bioconjugate Chemistry (2015)

Kaido Viht Siiri Saaver Jürgen Vahter Erki Enkvist Darja Lavõgina

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.

Peptoid

Conjugate

10.1021/acs.bioconjchem.5b00383

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Development of bisubstrate inhibitors for protein kinase CK2

Jürgen Vahter

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A subnanomolar fluorescent probe for protein kinase CK2 interaction studies

Organic & Biomolecular Chemistry (2012)

Erki Enkvist Kaido Viht N. Bischoff Jürgen Vahter Siiri Saaver

Up-regulation of an acidophilic protein kinase, CK2, has been established in several types of cancer. This cognition has made CK2 an important target for drug development for cancer chemotherapy. The characterization of potential drug candidates, determination of the structure and clarification of the functions of CK2 could be facilitated by the application of small-molecule fluorescent probes that bind to the active site of the enzyme with high affinity and selectivity. We have used a bisubstrate approach for the development of a highly potent inhibitor of CK2. 4,5,6,7-Tetrabromo-1H-benzimidazole was conjugated with peptides containing multiple aspartate residues via different linkers. The design of the inhibitors was by crystallographic analysis of the complex of an inhibitor with the catalytic subunit of the enzyme (CK2α). The inhibitory potency of the synthesized compounds was established in a kinetic assay that used thin layer chromatography for the measurement of the rate of phosphorylation of fluorescently labelled peptide 5-TAMRA-RADDSDDDDD. The most potent inhibitor, ARC-1502 (Ki = 0.5 nM), revealed high selectivity for CK2α in a panel of 140 protein kinases. Labelling of ARC-1502 with PromoFluor-647 gave the fluorescent probe ARC-1504 that possessed subnanomolar affinity towards both CK2α and the holoenzyme. The probe was used in a fluorescence anisotropy-based binding assay to measure the concentration of CK2α and characterize non-labelled ligands binding to the active site of CK2α.

Benzimidazole

10.1039/c2ob26022k

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Citations (35)