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      Computational Drug Repurposing Approach to Identify Novel Inhibitors of ILK Protein for Treatment of Esophageal Squamous Cell Carcinoma


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          Esophageal squamous cell cancer (ESCC) is a deadly malignant tumor characterized by an overall 5-year survival rate below 20%, with China accounting for approximately 50% of all cases worldwide. Our previous studies have demonstrated that high integrin-linked kinase (ILK) expression plays a key role in development and progression of ESCC both in vitro and in vivo. Here, we employed the drug repurposing approach to identify a novel FDA-approved anticancer inhibitor against ILK-induced tumorigenesis and progression.


          We screened the ZINC15 database and predicted the molecular docking ability among FDA-approved and publicly available drugs to ILK and then performed computational docking and visual inspection analyses of the top 10 ranked drugs. Two computer-based virtual screened drugs were evaluated in vitro for their ability to directly bind purified ILK by surface plasmon resonance. Cytotoxicity of the two candidate drugs was validated in vitro using CCK-8 and LDH assays.


          We initially selected the top 10 compounds, based on their minimum binding energy to the ILK crystal, after molecular docking and subjected them to further screening. Taking the binding energy of −10 kcal/mol as the threshold, we selected two drugs, namely, nilotinib and teniposide, for the wet-lab experiment. Surface plasmon resonance (SPR) revealed that nilotinib and teniposide had equilibrium dissociation constant (KD) values of 6.410 E − 6 and 1.793 E − 6, respectively, which were lower than 2.643 E − 6 observed in ILK-IN-3 used as the positive control. The IC50 values for nilotinib and teniposide in ESCC cell lines were 40  μM and 200–400 nM, respectively. Results of the CCK-8 assay demonstrated that both nilotinib and teniposide significantly inhibited proliferation of cells ( P < 0.01). LDH results revealed that both drugs significantly suppressed the rate of cell death ( P < 0.01).


          The drug repositioning procedure can effectively identify new therapeutic tools for ESCC. Our findings suggest that nilotinib and teniposide are efficacious inhibitors of ILK and thus have potential to target ILK-mediated signaling pathways for management of ESCC.

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          Most cited references39

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.

            We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. (c) 2009 Wiley Periodicals, Inc.
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              Drug repurposing: progress, challenges and recommendations

              Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

                Author and article information

                J Oncol
                J Oncol
                Journal of Oncology
                29 December 2022
                : 2022
                Department of General Medicine of Healthy Care Center for Cadres, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
                Author notes

                Academic Editor: Shuanglin Qin

                Copyright © 2022 Juan Liu et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: National Natural Science Foundation of China
                Award ID: 81860421
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy


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