Acetoxymethyl Ester of Tetrabromobenzimidazole-Peptoid Conjugate for Inhibition of Protein Kinase CK2 in Living Cells
| Autor: | Jürgen Vahter, Siiri Saaver, Barbara Guerra, Asko Uri, Darja Lavogina, Hedi Sinijärv, Erki Enkvist, Olaf-Georg Issinger, Gerda Raidaru, Kaido Viht |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular animal structures Cell Survival Biomedical Engineering Pharmaceutical Science Bioengineering MAP2K7 chemistry.chemical_compound Peptoids Live cell imaging Humans Protein phosphorylation Threonine Protein kinase A Casein Kinase II Protein Kinase Inhibitors Pharmacology Esterification fungi Organic Chemistry Peptoid chemistry Biochemistry embryonic structures Phosphorylation Benzimidazoles Casein kinase 2 Biotechnology HeLa Cells |
| Zdroj: | Viht, K, Saaver, S, Vahter, J, Enkvist, E, Lavogina, D, Sinijarv, H, Raidaru, G, Guerra, B, Issinger, O-G & Uri, A 2015, ' Acetoxymethyl ester of tetrabromobenzimidazole-peptoid conjugate for inhibition of protein kinase CK2 in living cells ', Bioconjugate Chemistry, vol. 26, no. 12, pp. 2324-2335 . https://doi.org/10.1021/acs.bioconjchem.5b00383 |
| ISSN: | 1520-4812 |
| DOI: | 10.1021/acs.bioconjchem.5b00383 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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