Design, Synthesis and Structure-Activity Relationship Studies of Protein Kinase CK2 Inhibitors Containing a Purine Scaffold

Protein kinase CK2 (CK2) is involved in the suppression of gene expression, protein synthesis, cell proliferation, and apoptosis, thus making it a target protein for the development of therapeutics toward cancer, nephritis, and coronavirus disease 2019. Using the solvent dipole ordering-based method for virtual screening, we identified and designed new candidate CK2 alpha inhibitors containing purine scaffolds. Virtual docking experiments supported by experimental structure-activity relationship studies identified the importance of the 4-carboxyphenyl group at the 2-position, a carboxamide group at the 6-position, and an electron-rich phenyl group at the 9-position of the purine scaffold. Docking studies based on the crystal structures of CK2 alpha and inhibitor (PDBID: 5B0X) successfully predicted the binding mode of 4-(6-carbamoyl-8-oxo-9-phenyl- 8,9dihydro-7H-purin-2-yl) benzoic acid (11), and the results were used to design stronger small molecule targets for CK2 alpha inhibition. Interaction energy analysis suggested that 11 bound around the hinge region without the water molecule (W1) near Trp176 and Glu81 that is frequently reported in crystal structures of CK2 alpha inhibitor complexes. X-ray crystallographic data for 11 bound to CK2 alpha was in very good agreement with the docking experiments, and consistent with activity. From the structure- activity relationship (SAR) studies presented here, 4-(6- Carbamoyl-9-(4-(dimethylamino)phenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl) benzoic acid (12) was identified as an improved active purine-based CK2 alpha inhibitor with an IC50 of 4.3 mu M. These active compounds with an unusual binding mode are expected to inspire new CK2 alpha inhibitors and the development of therapeutics targeting CK2 inhibition. Key words protein kinase CK2, CK2

Automated summary

In this study, new candidate CK2α inhibitors with purine scaffolds were designed and identified using a solvent dipole ordering-based method for virtual screening. The importance of specific groups at different positions on the purine scaffold was supported by virtual docking experiments and experimental structure-activity relationship studies. The results successfully predicted the binding mode of a strong small molecule inhibitor for CK2α and these findings are expected to inspire the development of new CK2α inhibitors with unique binding modes.