Biological properties and structural study of new aminoalkyl derivatives of benzimidazole and benzotriazole, dual inhibitors of CK2 and PIM1 kinases.
The new aminoalkyl-substituted derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) were synthesized, and their influence on the activity of recombinant human CK2 α, CK2 holoenzyme and PIM1 kinases was evaluated. All derivatives inhibited the activity of studied kinases and the most efficient were aminopropyl-derivatives 8b and 14b. These compounds also exerted inhibition of cancer cell lines - CCRF-CEM (acute lymphoblastoid leukemia), MCF-7 (human breast cancer), and PC-3 (prostate cancer) proliferation and their EC50 is comparable with the value for clinically studied CK2 inhibitor CX-4945. Preliminary structure activity relationship analysis indicated that the spacer length affected antitumor potency, and two to three methylene units were more favorable. The complex of CK2 α1-335/8b was crystallized, both under high-salt conditions and under low-salt conditions giving crystals which diffracted X-rays to about 2.4 Å resolution, what enabled the determination of the corresponding 3D-structures.
['Chojnacki|K|K|', 'Wińska|P|P|', 'Wielechowska|M|M|', 'Łukowska-Chojnacka|E|E|', 'Tölzer|C|C|', 'Niefind|K|K|', 'Bretner|M|M|']
D001562:Benzimidazoles D001665:Binding Sites D047390:Casein Kinase II D045744:Cell Line, Tumor D049109:Cell Proliferation D018360:Crystallography, X-Ray D006801:Humans D056004:Molecular Dynamics Simulation D010766:Phosphorylation D047428:Protein Kinase Inhibitors D017434:Protein Structure, Tertiary D051573:Proto-Oncogene Proteins c-pim-1 D011994:Recombinant Proteins D013329:Structure-Activity Relationship D014230:Triazoles
Structural study ATP-competitive inhibitors Antiproliferative activity Casein kinase 2 CK2 Protein kinase PIM1