Synthesis, Biological Properties And Structural Study Of New Halogenated Azolo [4,5-B]Pyridines As Inhibitors Of Ck2 Kinase

The new halogenated 1H-triazolo [4,5-b] pyridines and 1H-imidazo [4,5-b] pyridines were synthesised as analogues of known CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) and 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi). Their influence on the activity of recombinant human CK2 alpha, CK2 alpha' and PIM1 kinases was determined. The most active inhibitors were di- and trihalogenated 1H-triazolo [4,5-bl pyridines (4a, 5a and 10a) with IC50 values 2.56, 3.82 and 3.26 mu M respectively for CK2 alpha. Furthermore, effect on viability of cancer cell lines MCF-7 (human breast adenocarcinoma) and CCRF-CEM (T lymphoblast leukemia) of all final compounds was evaluated. Finally, three crystal structures of complexes of CK2 alpha(1-335) with inhibitors 4a, 5a and 10a were obtained. In addition, new protocol was used to obtain high-resolution crystal structures of CK2 alpha'(Cys336Ser) in complex with four inhibitors (4a, 5a, 5b, 10a).