A novel class of selective CK2 inhibitors targeting its open hinge conformation

Eur J Med Chem. 2020 Jun 1;195:112267. doi: 10.1016/j.ejmech.2020.112267. Epub 2020 Mar 25.


Protein kinase CK2 sustains cancer growth, especially in hematological malignancies. Its inhibitor SRPIN803, based on a 6-methylene-5-imino-1,3,4-thiadiazolopyrimidin-7-one scaffold, showed notable specificity. Our synthesis of the initially proposed SRPIN803 resulted in its constitutional isomer SRPIN803-revised, where the 2-cyano-2-propenamide group does not cyclise and fuse to the thiadiazole ring. Its crystallographic structure in complex with CK2α identifies the structural determinants of the reported specificity. SRPIN803-revised explores the CK2 open hinge conformation, extremely rare among kinases, also interacting with side chains from this region. Its optimization lead to the more potent compound 4, which inhibits endocellular CK2, significantly affects viability of tumour cells and shows remarkable selectivity on a panel of 320 kinases.

Keywords: Chemical synthesis and structural characterization; Endocellular assay and mechanism of action; Protein kinase CK2; X-ray crystallography.

MeSH terms

  • Casein Kinase II / antagonists & inhibitors*
  • Casein Kinase II / chemistry*
  • Casein Kinase II / metabolism
  • Drug Design*
  • Humans
  • Jurkat Cells
  • Molecular Docking Simulation
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidinones / chemistry
  • Pyrimidinones / metabolism
  • Pyrimidinones / pharmacology
  • Structure-Activity Relationship
  • Thiadiazoles / chemistry
  • Thiadiazoles / metabolism
  • Thiadiazoles / pharmacology


  • Protein Kinase Inhibitors
  • Pyrimidinones
  • SRPIN803
  • Thiadiazoles
  • Casein Kinase II