The pleiotropic nature, role in many cellular processes, and constitutive activity of protein kinase CK2 exemplify its importance in a number of diseases, e.g. thrombosis and cancer. Compounds developed in this paper represent a novel class of biologically active scaffold that may be developed into promising drug candidates, but also applied to study the yet still unspecified pathways regulated by CK2. Biligand inhibitors of CK2 were constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and carboxylate-rich peptoids. Compound ARC-772 (Kd,CK2 = 0.3 nM) revealed good inhibitory selectivity towards CK2 in a panel of 140 protein kinases (Gini coefficient of 0.752). Esterification of the negatively charged carboxylate groups enhanced the cellular uptake - approximately 100 μM intracellular concentration was obtained. A distinctive specificity between cancerous HeLa cells and non-cancerous CHO cells of ARC-772 to activate caspase-3 was demonstrated. ARC-772 possessed remarkable 20-fold lower EC50 value for HeLa cells compared to reference compound CX-4945. Finally, this paper demonstrated for the first time the effective inhibition of ADP-induced platelet aggregation after treatment with biligand inhibitor of CK2.

作者：Hedi, Rahnel；Kaido, Viht；Darja, Lavogina；Olga, Mazina；T?iv, Haljasorg；Erki, Enkvist；Asko, Uri

来源：ChemMedChem 2017 年