Pro-Apoptotic Activity of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one, an Intracellular Inhibitor of PIM-1 Kinase in Acute Lymphoblastic Leukemia and Breast Cancer Cells
Abstract
1. Introduction
2. Results
2.1. Synthesis
2.2. Biological Evaluation
2.2.1. Determination of the Inhibitory Activity of Compounds 1–4 Towards CK2 and PIM-1 Kinases
2.2.2. Cytotoxic Effect of TBBi Derivatives Toward Cancer Cell Lines, CCRF-CEM, MCF-7, and MDA-MB-231, and Non-Cancerous Vero Cells
2.2.3. Induction of Apoptosis in CCRF-CEM and MCF-7 Cells
2.2.4. Mitochondrial Membrane Potential (ΔΨm) in CCRF-CEM and MCF-7
2.2.5. The Effect of Cpd. 1 and TBBi on Cell Cycle Progression in CCRF-CEM and MCF-7 Cells
2.2.6. Activation of Caspase-3 in CCRF-CEM
2.2.7. Intracellular Inhibition of CK2 and PIM-1 Kinases in CCRF-CEM and MCF-7 Cells
2.3. Molecular Modeling
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Chemical Study
4.2.1. Synthesis of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one (1)
4.2.2. Synthesis of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-ol (2)
4.3. Biological Assays
4.3.1. Reagents and Antibodies
4.3.2. Cloning, Expression, and Purification of Human CK2α, holoCK2, and PIM-1
4.3.3. Inhibition of Recombinant CK2 and PIM-1
4.3.4. Cell Culture and Agents’ Treatment
4.3.5. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT)-Based Viability Assay
4.3.6. Detection of Apoptosis by Annexin V/Propidium Iodide (PI) Labelling
4.3.7. Mitochondrial Membrane Potential (ΔΨm) Assay
4.3.8. Caspase-3 Activation
4.3.9. Detection of Cell Cycle Progression by Flow Cytometry
4.3.10. Western Blotting
4.3.11. Densitometry
4.3.12. PhosFlow Analysis
4.3.13. Statistical Evaluation
4.4. In Silico Studies
4.4.1. Molecular Docking
4.4.2. Molecular Dynamics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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CK2α | PIM-1 | ||||
---|---|---|---|---|---|
Cpd. | Cpd. Concentration [μM] | Residual Activity [%] | IC50 [μM] | Residual Activity [%] | IC50 [μM] |
1 | 2 | 58.5 ± 2.2 | 6.65 ± 0.74 | 22.4 ± 0.9 | 0.52 ± 0.02 |
5 | 32.3 ± 0.3 | 10.3 ± 0.7 | |||
20 | 10.2 ± 0.6 | 2.9 ± 0.2 | |||
2 | 2 | 70.9 ± 0.9 | 11.05 ± 0.15 | 58.0 ± 2.4 | 2.41 ± 0.29 |
5 | 41.8 ± 2.3 | 26.4 ± 1.7 | |||
20 | 20.1 ± 1.2 | 9.3 ± 0.3 | |||
3 | 2 | 101.7 ± 8.9 | - | 82.5 ± 4.2 | - |
5 | 89.2 ± 8.6 | 67.4 ± 0.7 | |||
20 | 82.8 ± 15.4 | 62.6 ± 0.8 | |||
4 | 2 | 72.1 ± 3.0 | - | 66.9 ± 1.1 | 3.08 ± 0.07 |
5 | 21.3 ± 1.9 | 29.1 ± 0.1 | |||
20 | 15.6 ± 0.3 | 21.4 ± 0.2 | |||
TBBi | 1.16 ± 0.09 | 0.53 ± 0.04 |
Cpd. | IC50 [µM] | SI * | |||||
---|---|---|---|---|---|---|---|
CCRF-CEM | MCF-7 | MDA-MB-231 | Vero | CCRF-CEM | MCF-7 | MDA-MB-231 | |
1 | 12.43 ± 0.82 | 17.09 ± 2.07 | 21.20 ± 0.76 | 20.20 ± 3.59 | 1.62 | 1.18 | 0.95 |
2 | 58.24 ± 5.86 | 18.42 ± 0.41 | 28.17 ± 3.27 | 96.06 ± 4.76 | 1.65 | 5.21 | 3.4 |
4 | 75.26 ± 10.30 | 41.86 ± 8.37 | >200 | 132.00 ± 19.36 | 1.75 | 3.15 | - |
TBBi | 17.56 ± 0.67 | 12.61 ± 2.72 | 29.71 ± 2.23 | 24.80 ± 0.90 | 1.41 | 1.97 | 0.83 |
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Wińska, P.; Wielechowska, M.; Milewski, Ł.; Siedlecki, P.; Łukowska-Chojnacka, E. Pro-Apoptotic Activity of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one, an Intracellular Inhibitor of PIM-1 Kinase in Acute Lymphoblastic Leukemia and Breast Cancer Cells. Int. J. Mol. Sci. 2025, 26, 5897. https://doi.org/10.3390/ijms26125897
Wińska P, Wielechowska M, Milewski Ł, Siedlecki P, Łukowska-Chojnacka E. Pro-Apoptotic Activity of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one, an Intracellular Inhibitor of PIM-1 Kinase in Acute Lymphoblastic Leukemia and Breast Cancer Cells. International Journal of Molecular Sciences. 2025; 26(12):5897. https://doi.org/10.3390/ijms26125897
Chicago/Turabian StyleWińska, Patrycja, Monika Wielechowska, Łukasz Milewski, Paweł Siedlecki, and Edyta Łukowska-Chojnacka. 2025. "Pro-Apoptotic Activity of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one, an Intracellular Inhibitor of PIM-1 Kinase in Acute Lymphoblastic Leukemia and Breast Cancer Cells" International Journal of Molecular Sciences 26, no. 12: 5897. https://doi.org/10.3390/ijms26125897
APA StyleWińska, P., Wielechowska, M., Milewski, Ł., Siedlecki, P., & Łukowska-Chojnacka, E. (2025). Pro-Apoptotic Activity of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one, an Intracellular Inhibitor of PIM-1 Kinase in Acute Lymphoblastic Leukemia and Breast Cancer Cells. International Journal of Molecular Sciences, 26(12), 5897. https://doi.org/10.3390/ijms26125897