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Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines

1
PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
2
Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
3
Department of Pediatrics, Taipei Medical University Hospital, Taipei 11031, Taiwan
4
Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
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Department of Medicine, School of Medicine, College of Medicine, 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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The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
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Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
9
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
10
School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan
11
PhD Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomedicines 2021, 9(1), 92; https://doi.org/10.3390/biomedicines9010092
Received: 26 December 2020 / Revised: 16 January 2021 / Accepted: 18 January 2021 / Published: 19 January 2021
Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein–ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy. View Full-Text
Keywords: protein-ligand interaction; molecular docking simulation; target identification; small-molecule derivatives of salicylanilide; drug discovery; drug development protein-ligand interaction; molecular docking simulation; target identification; small-molecule derivatives of salicylanilide; drug discovery; drug development
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MDPI and ACS Style

Lawal, B.; Liu, Y.-L.; Mokgautsi, N.; Khedkar, H.; Sumitra, M.R.; Wu, A.T.H.; Huang, H.-S. Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines. Biomedicines 2021, 9, 92. https://doi.org/10.3390/biomedicines9010092

AMA Style

Lawal B, Liu Y-L, Mokgautsi N, Khedkar H, Sumitra MR, Wu ATH, Huang H-S. Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines. Biomedicines. 2021; 9(1):92. https://doi.org/10.3390/biomedicines9010092

Chicago/Turabian Style

Lawal, Bashir, Yen-Lin Liu, Ntlotlang Mokgautsi, Harshita Khedkar, Maryam R. Sumitra, Alexander T.H. Wu, and Hsu-Shan Huang. 2021. "Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines" Biomedicines 9, no. 1: 92. https://doi.org/10.3390/biomedicines9010092

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