Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer
Abstract
:1. Introduction
2. Results
2.1. Rational Design of Novel Potent N-Myc Inhibitors
2.1.1. Homology Modelling of N-Myc-Max Heterodimer
2.1.2. Identification of Scaffolds Targeting the N-Myc-Max DBD Site
2.2. Structure-Based Drug Design of N-Myc and AURKA Dual-Inhibitors
2.3. Binding Prediction of 70812 to AURKA and N-Myc through Docking
2.4. Experimental Validation of 70812 As Dual-Inhibitor
N′-[4-cyano-2-(trifluoromethyl)phenyl]-4-(trifluoromethyl)benzohydrazide as Active Scaffold against N-Myc
2.5. Biological Characterization of 70812 as a Dual-Inhibitor
2.5.1. 70812 Is a Potent Inhibitor of Both N-Myc and AURKA
2.5.2. 70812 Reduces Growth of LNCaP and 22Rv1 Cells in a Dose-Dependent Manner
3. Discussion
4. Materials and Methods
4.1. In Silico Experiments
4.1.1. Homology Modelling of N-Myc-Max Heterodimer
4.1.2. Protein and Ligand Preparation
4.1.3. Molecular Docking
4.1.4. Molecular Dynamics Simulations
4.2. In Vitro Evaluation of Hit Compounds
4.2.1. eGFP Cellular Myc Transcription Assay
4.2.2. Cell Viability Assays
4.2.3. Aurora A Kinase Activity Assay
4.2.4. Biolayer Interferometry Assay
5. Conclusions
6. Patent
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AR | Androgen receptor |
AURKA | Aurora A kinase |
bHLHLZ | basic helix-loop-helix leucine zipper |
BLI | bio-layer interferometry |
CRPC | castration-resistant prostate cancer |
DBD | DNA-binding domain |
NEPC | neuroendocrine prostate cancer |
PCa | prostate cancer |
RMSD | Root-Mean Square Deviation |
MD | Molecular dynamics |
Appendix A
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Ton, A.-T.; Singh, K.; Morin, H.; Ban, F.; Leblanc, E.; Lee, J.; Lallous, N.; Cherkasov, A. Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer. Int. J. Mol. Sci. 2020, 21, 8277. https://doi.org/10.3390/ijms21218277
Ton A-T, Singh K, Morin H, Ban F, Leblanc E, Lee J, Lallous N, Cherkasov A. Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer. International Journal of Molecular Sciences. 2020; 21(21):8277. https://doi.org/10.3390/ijms21218277
Chicago/Turabian StyleTon, Anh-Tien, Kriti Singh, Hélène Morin, Fuqiang Ban, Eric Leblanc, Joseph Lee, Nada Lallous, and Artem Cherkasov. 2020. "Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer" International Journal of Molecular Sciences 21, no. 21: 8277. https://doi.org/10.3390/ijms21218277