mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2',4'-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications

Bashir Lawal; Ching-Yu Lee; Ntlotlang Mokgautsi; Maryam Rachmawati Sumitra; Harshita Khedkar; Alexander T H Wu; Hsu-Shan Huang

doi:10.3389/fonc.2021.656738

mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2',4'-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications

Front Oncol. 2021 Mar 26:11:656738. doi: 10.3389/fonc.2021.656738. eCollection 2021.

Authors

Bashir Lawal^{1

2}, Ching-Yu Lee^{3

4}, Ntlotlang Mokgautsi^{1

2}, Maryam Rachmawati Sumitra^{1

2}, Harshita Khedkar^{1

2}, Alexander T H Wu^{5

6

7

8}, Hsu-Shan Huang^{1

2

8

9

10}

Affiliations

¹ PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
² Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
³ Department of Orthopedics, Taipei Medical University Hospital, Taipei, Taiwan.
⁴ Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
⁶ The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁷ Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
⁸ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
⁹ School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
¹⁰ PhD Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.

Abstract

Background: The application of computational and multi-omics approaches has aided our understanding of carcinogenesis and the development of therapeutic strategies. NSC765598 is a novel small molecule derivative of salicylanilide. This study aims to investigate the ligand-protein interactions of NSC765598 with its potential targets and to evaluate its anticancer activities in vitro.

Methods: We used multi-computational tools and clinical databases, respectively, to identify the potential drug target for NSC765598 and analyze the genetic profile and prognostic relevance of the targets in multiple cancers. We evaluated the in vitro anticancer activities against the National Cancer Institute 60 (NCI60) human tumor cell lines and used molecular docking to study the ligand-protein interactions. Finally, we used the DTP-COMPARE algorithm to compare the NSC765598 anticancer fingerprints with NCI standard agents.

Results: We identified mammalian target of rapamycin (mTOR)/epidermal growth factor receptor (EGFR)/inducible nitric oxide synthase (iNOS)/mitogen-activated protein 2 kinase 1 (MAP2K1)/fibroblast growth factor receptor (FGFR)/transforming growth factor-β1 (TGFB1) as potential targets for NSC765598. The targets were enriched in cancer-associated pathways, were overexpressed and were of prognostic relevance in multiple cancers. Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non-small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered. NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI₅₀) = 1.12-3.95 µM; total growth inhibition (TGI) = 3.72-16.60 μM), leukemia (GI₅₀ = 1.20-3.10 µM; TGI = 3.90-12.70 μM), melanoma (GI₅₀ = 1.45-3.59 µM), and renal cancer (GI₅₀ = 1.38-3.40 µM; TGI = 4.84-13.70 μM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598. Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of π-interactions, with higher preferences for EGFR (ΔG = -11.0 kcal/mol), NOS2 (ΔG = -11.0 kcal/mol), and mTOR (ΔG = -8.8 kcal/mol). NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.

Conclusion: NSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.

Keywords: NSC765598; anticancer activity; molecular docking; multi-omics study; multi-target small molecule; protein-ligand interaction.