Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
2.2. Enzyme Inhibition Activity
2.3. Molecular Modeling Studies
2.4. 2D and 3D Cytotoxicity Studies
2.5. In Cell Mechanistic Studies
2.6. In Vivo Studies
3. Materials and Methods
3.1. Chemistry
3.1.1. General Methods
3.1.2. General Procedure for the Synthesis of (5-Bromo-1H-indol-3-yl)oxo-acetyl Chloride (3b)
3.1.3. General Procedure for the Preparation of Bis(1H-indol-3-yl)ethane-1,2-diones (4a–ab)
3.1.4. General Procedure for the Preparation of 5,6-di(1H-Indol-3-yl)-1,2,4-triazin-3-amine (5–6)
3.2. Software Overview
3.3. PDK 1–4 Kinase Assay
3.4. Heat Shock Protein 90 (HSP90) Inhibition Assay
3.5. Experiments with Cultured Human Cancer Cells
3.6. Cell Cultures
3.7. MTT Assay
3.8. Spheroid Cultures
3.9. Acid Phosphatase (APH) Assay
3.10. Cellular PDH Phosphorylation
3.11. Cellular Oxygen Consumption
3.12. Cellular Lactate Production
3.13. Mitochondrial Membrane Potential (ΔΨ)
3.14. ROS Production
3.15. Quantification of Thiols
3.16. TEM Analysis
3.17. Caspase Activity
3.18. Cell Death Induction
3.19. In Vivo Anticancer Activity
3.20. PDH Phosphorylation in Mice Tumor Tissues
3.21. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cpd | IC50 (µM) ±S.D. PDK1 |
---|---|
5i | 0.06 ± 0.02 |
5k | 0.01 ± 0.003 |
5l | 0.03 ± 0.004 |
5w | 0.1 ± 0.04 |
6h | 0.08 ± 0.01 |
6j | 0.07 ± 0.02 |
6s | 0.09 ± 0.04 |
DCA | >100 |
DAP | >100 |
Cpd | IC50 (µM) ±S.D. PSN-1 | IC50 (µM) ±S.D. BxPC-3 | Cpd | IC50 (µM) ±S.D. PSN-1 | IC50 (µM) ±S.D. BxPC-3 |
---|---|---|---|---|---|
5b | 0.5 ± 0.2 | 0.4 ± 0.1 | 6j | 0.6 ± 0.1 | 0.20 ± 0.04 |
5d | 0.30 ± 0.04 | 0.4 ± 0.1 | 6o | 0.40 ± 0.04 | 0.30 ± 0.03 |
5j | 0.4 ± 0.1 | 0.10 ± 0.04 | 6v | 0.20 ± 0.03 | 0.10 ± 0.02 |
5o | 0.5 ± 0.1 | 0.20 ± 0.03 | 6x | 0.30 ± 0.04 | 0.3 ± 0.1 |
5s | 0.5 ± 0.2 | 2.2 ± 0.6 | 6y | 0.60 ± 0.04 | 0.3 ± 0.1 |
5t | 0.4 ± 0.1 | 1.4 ± 0.2 | Gemcitabine | 0.10 ± 0.04 | 0.020 ± 0.003 |
5v | 0.20 ± 0.04 | 0.20 ± 0.03 | DCA | >1000 | >1000 |
5x | 0.3 ± 0.1 | 0.20 ± 0.04 | DAP | 10.2 ± 1.6 | 1.06 ± 0.9 |
Cpd | IC50 (µM) ±S.D. PSN-1 | IC50 (µM) ±S.D. BxPC-3 | Cpd | IC50 (µM) ±S.D. PSN-1 | IC50 (µM) ±S.D. BxPC-3 |
---|---|---|---|---|---|
5g | 5.8 ± 0.8 | 19.5 ± 2.1 | 6h | 24.3 ± 1.4 | 33.4 ± 3.6 |
5i | 4.9 ± 0.8 | 34.1 ± 1.5 | 6j | 18.1 ± 2.3 | 41.2 ± 3.6 |
5j | 10.4 ± 1.6 | 16.7 ±2.0 | 6k | 9.4 ± 0.2 | 22.3 ± 2.6 |
5k | 15.9 ± 2.3 | 67.9 ± 3.7 | 6l | 8.0 ± 0.1 | 8.8 ± 0.4 |
5l | 8.7 ± 0.5 | 52.1 ± 3.3 | 6s | 22.3 ± 2.3 | 29.2 ± 1.4 |
5q | 8.4 ± 0.5 | 8.6 ± 0.3 | Gemcitabine | 159.5 ± 5.6 | 102.6 ± 6.3 |
5u | 9.2 ± 0.7 | 16.6 ± 0.02 | DCA | >1000 | >1000 |
5w | 15.3 ± 2.8 | 12.2 ± 1.3 | DAP | 78.2 ± 6.8 | 87.4 ± 8.9 |
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Carbone, D.; De Franco, M.; Pecoraro, C.; Bassani, D.; Pavan, M.; Cascioferro, S.; Parrino, B.; Cirrincione, G.; Dall’Acqua, S.; Moro, S.; et al. Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2023, 24, 3679. https://doi.org/10.3390/ijms24043679
Carbone D, De Franco M, Pecoraro C, Bassani D, Pavan M, Cascioferro S, Parrino B, Cirrincione G, Dall’Acqua S, Moro S, et al. Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma. International Journal of Molecular Sciences. 2023; 24(4):3679. https://doi.org/10.3390/ijms24043679
Chicago/Turabian StyleCarbone, Daniela, Michele De Franco, Camilla Pecoraro, Davide Bassani, Matteo Pavan, Stella Cascioferro, Barbara Parrino, Girolamo Cirrincione, Stefano Dall’Acqua, Stefano Moro, and et al. 2023. "Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma" International Journal of Molecular Sciences 24, no. 4: 3679. https://doi.org/10.3390/ijms24043679