Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
Department für Chemie, Institut für Biochemie, Universtät zu Köln, Zülpicher Straße 47, D-50674 Köln, Germany.
Bioorg Chem. 2021 Jan;106:104502. doi: 10.1016/j.bioorg.2020.104502. Epub 2020 Nov 24.
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 CK2α, CK2α' and PIM1 kinases was determined. The most active inhibitors were di- and trihalogenated 1H-triazolo[4,5-b]pyridines (4a, 5a and 10a) with IC values 2.56, 3.82 and 3.26 μM respectively for CK2α. 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 CK2α with inhibitors 4a, 5a and 10a were obtained. In addition, new protocol was used to obtain high-resolution crystal structures of CK2α' in complex with four inhibitors (4a, 5a, 5b, 10a).
新的卤代 1H-三唑并[4,5-b]吡啶和 1H-咪唑并[4,5-b]吡啶被合成作为已知 CK2 抑制剂的类似物：4,5,6,7-四溴-1H-苯并三唑（TBBt）和 4,5,6,7-四溴-1H-苯并咪唑（TBBi）。它们对重组人 CK2α、CK2α'和 PIM1 激酶活性的影响进行了测定。最活跃的抑制剂是二卤代和三卤代 1H-三唑并[4,5-b]吡啶（4a、5a 和 10a），它们对 CK2α 的 IC 值分别为 2.56、3.82 和 3.26 μM。此外，还评估了所有最终化合物对 MCF-7（人乳腺癌腺癌细胞）和 CCRF-CEM（T 淋巴母细胞白血病）癌细胞系活力的影响。最后，获得了 CK2α 与抑制剂 4a、5a 和 10a 复合物的三个晶体结构。此外，还使用新的方案获得了 CK2α'与四种抑制剂（4a、5a、5b、10a）复合物的高分辨率晶体结构。
