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

Bioconjug Chem. 2015 Dec 16;26(12):2324-35. doi: 10.1021/acs.bioconjchem.5b00383. Epub 2015 Nov 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / metabolism
  • Cell Survival / drug effects
  • Esterification
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Peptoids / chemistry*
  • Peptoids / pharmacokinetics
  • Peptoids / pharmacology*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*


  • 4,5,6,7-tetrabromobenzimidazole
  • Benzimidazoles
  • Peptoids
  • Protein Kinase Inhibitors
  • CSNK2A1 protein, human
  • Casein Kinase II