Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Chemicals
2.2. In Silico Prediction of the Binding Affinity of Imidazole-4-N-acetamide Derivatives
2.2.1. Preparation of CDK–Ligand Complexes
2.2.2. NEQ Thermodynamics and Free Energy Calculations
2.3. In Vitro Kinase Assays
2.4. Relative Selectivity Calculation
2.5. Anti-Proliferative Activity of New Imidazole-4-N-acetamide Derivatives
2.6. Statistical Analysis
3. Results
3.1. Preparation of Starting Target–Ligand Complexes and Calculations of Binding Energies
3.2. CDK Inhibitory Potency of New Imidazole-4-N-acetamide Derivatives
3.3. Prediction of CDK Inhibitory Potency and Selectivity of Imidazole-4-N-acetamide Derivatives
3.4. Cytotoxicity of Novel Imidazole-4-N-acetamide Derivatives
4. Discussion
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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Target | Compound 1 | Compound 2 | Compound 3 | Compound 4 | PHA-793887 |
---|---|---|---|---|---|
CDK1/cyclin E | 14 (8–27) | 0.72 (0.54–0.96) | 30 (19–49) | 6.2 (4.0–9.9) | 0.060 (cyclin B) |
CDK2/cyclin E | 0.71 (0.64–0.80) | 0.16 (0.13–0.19) | 1.2 (1.0–1.3) | 0.27 (0.24–0.31) | 0.008 |
CDK5/p35 | 40 (27–59) | 0.88 (0.65–1.19) | 79 (49–126) | 20 (16–25) | 0.006 (p25) |
CDK9/cyclin K | 3.0 (1.7–5.3) | 1.0 (0.7–1.5) | 4.3 (3.0–6.1) | 0.88 (0.83–0.94) | 0.138 (cyclin T1) |
Cell Line | Compound 2 | Compound 4 |
---|---|---|
SKOV-3 | 4.4 ± 1.2 | 3.3 ± 0.2 |
OVCAR-3 | 6.9 ± 0.5 | 5.8 ± 0.4 |
OV-90 | 3.9 ± 0.6 | 2.4 ± 0.3 |
UWB1.289 | 2.1 ± 0.2 | 1.7 ± 0.1 |
IMR-32 | 4.2 ± 0.1 | 3.2 ± 0.1 |
Kelly | 8.6 ± 2.1 | 9.2 ± 2.4 |
SH-SY5Y | 55.9 ± 3.7 | 57.8 ± 8.4 |
HELF | >100 | >100 |
MSC | >100 | >100 |
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Rusina, P.; Gandalipov, E.; Abdusheva, Y.; Panova, M.; Burdenkova, A.; Chaliy, V.; Brachs, M.; Stroganov, O.; Guzeeva, K.; Svitanko, I.; et al. Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases. Cancers 2023, 15, 3766. https://doi.org/10.3390/cancers15153766
Rusina P, Gandalipov E, Abdusheva Y, Panova M, Burdenkova A, Chaliy V, Brachs M, Stroganov O, Guzeeva K, Svitanko I, et al. Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases. Cancers. 2023; 15(15):3766. https://doi.org/10.3390/cancers15153766
Chicago/Turabian StyleRusina, Polina, Erik Gandalipov, Yana Abdusheva, Maria Panova, Alexandra Burdenkova, Vasiliy Chaliy, Maria Brachs, Oleg Stroganov, Ksenia Guzeeva, Igor Svitanko, and et al. 2023. "Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases" Cancers 15, no. 15: 3766. https://doi.org/10.3390/cancers15153766