Chojnacki Konrad, Wińska Patrycja, Skierka Katarzyna, Wielechowska Monika, Bretner Maria
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
Bioorg Chem. 2017 Jun;72:1-10. doi: 10.1016/j.bioorg.2017.02.017. Epub 2017 Mar 16.
Protein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as a promising target in anticancer therapy. New derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) bearing azide or substituted triazole groups were synthesized. Their influence on the activity of human recombinant CK2α and cytotoxicity against normal and cancer cell lines were evaluated. TBBi derivatives with triazole substituted with carboxyl substituent (7 and 10) exhibited the most potent inhibitory activity against CK2 with K value in the range of 1.96-0.91μM, respectively. New TBBi derivatives 2, 3, 5 and 9 have demonstrated the EC, in the range of 12-25μM and 13-29μM respectively towards CCRF-CEM and MCF-7 cells. Derivatives TBBi decreased viability of cancer cells more efficiently than BALB cells and the biggest differences were observed for the azide substituted compounds 3 and 5. The effect of the most active compounds on the activity of eight off-target kinases was evaluated. Inhibitory efficiency of CK2-mediated p65 phosphorylation was demonstrated for the TBBi and compound 12.
蛋白激酶2（CK2）是丝氨酸/苏氨酸激酶家族的成员，已被确立为抗癌治疗中一个有前景的靶点。合成了已知的CK2抑制剂4,5,6,7-四溴-1H-苯并咪唑（TBBi）和4,5,6,7-四溴-1H-苯并三唑（TBBt）带有叠氮基或取代三唑基的新衍生物。评估了它们对人重组CK2α活性的影响以及对正常细胞系和癌细胞系的细胞毒性。三唑被羧基取代的TBBi衍生物（7和10）对CK2表现出最有效的抑制活性，K值分别在1.96 - 0.91μM范围内。新的TBBi衍生物2、3、5和9对CCRF - CEM细胞和MCF - 7细胞的EC50分别在12 - 25μM和13 - 29μM范围内。TBBi衍生物比BALB细胞更有效地降低癌细胞的活力，并且对于叠氮基取代的化合物3和5观察到最大差异。评估了最具活性的化合物对八种脱靶激酶活性的影响。TBBi和化合物12显示出对CK2介导的p65磷酸化的抑制效率。
