Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy
Abstract
:1. Introduction
2. Results and Discussion
2.1. Structure-Based Virtual Screening of Novel Hit ENPP1 Inhibitors
2.2. Synthesis of the Candidate Compounds
2.3. Inhibition of ENPP1 Enzyme Activity by Compound 4a–h
2.4. Cellular ENPP1 Inhibitory Activity by Compound 4a–h
2.5. Binding-Mode Analysis
2.6. Cell Viability Assays
2.7. Molecular Mechanisms of Activity for Compound 4e
3. Materials and Methods
3.1. Materials and Reagents
3.2. Structure-Based Virtual Screening
3.3. Expression and Purification of Recombinant Human ENPP1
3.4. Chemistry Methods
3.5. Enzyme-Based ENPP1 Inhibitory Assays
3.6. Cellular ENPP1 Enzymatic Inhibition Assays
3.7. Molecular Docking Study
3.8. Cell Culture and Proliferation Assays
3.9. Pharmacological Research on ENPP1 Inhibitors in Mice
4. 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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Cpd. | -CDOCKER_ ENERGY | Cpd. | -CDOCKER_ ENERGY |
---|---|---|---|
4a | 33.483 | 4b | 34.596 |
4c | 35.391 | 4d | 39.904 |
4e | 34.405 | 4f | 33.617 |
4g | 33.616 | 4h | 33.293 |
Cpd. | Inhibition (%) @ 10 μM | Cpd. | Inhibition (%) @ 10 μM |
---|---|---|---|
4a | 72.2 | 4b | 76.5 |
4c | 75.4 | 4d | 92.6 |
4e | 90.5 | 4f | 52.9 |
4g | 72.7 | 4h | 55.5 |
Codes | 4T1 | LO2 | 293T |
---|---|---|---|
Compound 4e | 2.99 μM | 15.33% | 9.35% |
Cisplatin | 3.2 μM | 57% | 52% |
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Wang, X.; Lu, X.; Yan, D.; Zhou, Y.; Tan, X. Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy. Int. J. Mol. Sci. 2022, 23, 7104. https://doi.org/10.3390/ijms23137104
Wang X, Lu X, Yan D, Zhou Y, Tan X. Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy. International Journal of Molecular Sciences. 2022; 23(13):7104. https://doi.org/10.3390/ijms23137104
Chicago/Turabian StyleWang, Xiang, Xing Lu, Daojing Yan, Yajun Zhou, and Xiangshi Tan. 2022. "Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy" International Journal of Molecular Sciences 23, no. 13: 7104. https://doi.org/10.3390/ijms23137104