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In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1

1
PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Academia Sinica, Taipei 11031, Taiwan
2
Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
3
Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
4
The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
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Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 23561, Taiwan
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Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
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TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
10
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
11
National Defense Medical Center, School of Pharmacy, Taipei 11490, Taiwan
12
PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Giuseppe Damante
Int. J. Mol. Sci. 2021, 22(11), 5895; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115895
Received: 3 April 2021 / Revised: 26 May 2021 / Accepted: 27 May 2021 / Published: 31 May 2021
(This article belongs to the Special Issue Genetic Alterations in Tumors)
Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease’s pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI50 = 1.6 µM~1.82 µM and TGI50 = 3.5 µM~3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma. View Full-Text
Keywords: ovarian carcinoma; prognostic gene signature; bioinformatics; genetic alterations; drug resistance; protein-ligand interactions; target-based structure discovery ovarian carcinoma; prognostic gene signature; bioinformatics; genetic alterations; drug resistance; protein-ligand interactions; target-based structure discovery
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MDPI and ACS Style

Khedkar, H.N.; Wang, Y.-C.; Yadav, V.K.; Srivastava, P.; Lawal, B.; Mokgautsi, N.; Sumitra, M.R.; Wu, A.T.H.; Huang, H.-S. In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1. Int. J. Mol. Sci. 2021, 22, 5895. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115895

AMA Style

Khedkar HN, Wang Y-C, Yadav VK, Srivastava P, Lawal B, Mokgautsi N, Sumitra MR, Wu ATH, Huang H-S. In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1. International Journal of Molecular Sciences. 2021; 22(11):5895. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115895

Chicago/Turabian Style

Khedkar, Harshita N., Yu-Chi Wang, Vijesh K. Yadav, Prateeti Srivastava, Bashir Lawal, Ntlotlang Mokgautsi, Maryam R. Sumitra, Alexander T.H. Wu, and Hsu-Shan Huang. 2021. "In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1" International Journal of Molecular Sciences 22, no. 11: 5895. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115895

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