Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole

Mario A. Pagano, Mariola Andrzejewska, Maria Ruzzene, Stefania Sarno, Luca Cesaro, Jenny Bain, Matthew Elliott, Flavio Meggio, Zygmunt Kazimierczuk (Lead / Corresponding author), Lorenzo A. Pinna (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    172 Citations (Scopus)


    Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Thus, CK2 inhibitors designed to dissect the signaling pathways affected by this kinase, in perspective, may give rise to pharmacological tools. One of the most successful CK2 inhibitors is TBB (4,5,6,7-tetrabromobenzotriazole). Here we show that its inhibitory properties can be markedly improved by generating adducts in which N2 is replaced by a carbon atom bound to a variety of polar functions. The most efficient inhibitor is 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (2c) followed by the methylsulfanyl (8), isopropylamino (2e), and amino (2a) congeners. All these compounds display K(i) values <100 nM (40 nM in the case of 2c). 2c induces apoptosis of Jurkat cells more readily than TBB (DC50 value 2.7 vs 17 µM) and, unlike TBB, it does not display any side effect on mitochondria polarization up to 10 µM concentration. Molecular modeling of the CK2-2c complex, based on the crystal structure of the CK2-TBB complex suggests that a number of additional apolar contacts between its two methyl groups and hydrophobic residues nearby could account for its superior inhibitory properties. Consequently, 2c is even more susceptible than TBB to mutations of the unique hydrophobic residues V66 and/or I174 to alanine. We propose to adopt 2c as first choice CK2 inhibitor instead of TBB, especially for in cell studies.

    Original languageEnglish
    Pages (from-to)6239-6247
    Number of pages9
    JournalJournal of Medicinal Chemistry
    Issue number25
    Publication statusPublished - 1 Dec 2004


    • Animals
    • Apoptosis
    • Benzimidazoles/chemical synthesis
    • Casein Kinase II/antagonists & inhibitors
    • Catalytic Domain
    • Humans
    • Jurkat Cells
    • Kinetics
    • Models, Molecular
    • Molecular Structure
    • Mutation
    • Phosphorylation
    • Rats
    • Structure-Activity Relationship


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