Computational Drug Repurposing Approach to Identify Novel Inhibitors of ILK Protein for Treatment of Esophageal
Juan Liu1, Xiaoli Ma1, Leiyu Cao1
1Department of General Medicine of Healthy Care Center for Cadres, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China.
Purpose:
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.
Methods:
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.
Results:
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 6.410E - 6 and 1.793E - 6, respectively, which were lower than 2.643E - 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).
Conclusion:
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.
Insights
Drug repurposing identified nilotinib and teniposide as effective inhibitors of integrin-linked kinase (ILK) for esophageal squamous cell cancer (ESCC). These drugs show potential for treating ESCC by targeting ILK-mediated pathways.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Esophageal squamous cell cancer (ESCC) has a poor prognosis, with high integrin-linked kinase (ILK) expression linked to its development and progression.
- China bears a significant burden of ESCC, accounting for approximately 50% of global cases.
Purpose of the Study:
- To identify novel FDA-approved anticancer inhibitors for ILK-induced tumorigenesis and progression in ESCC using a drug repurposing strategy.
- To evaluate the efficacy of identified drugs in targeting ILK in ESCC models.
Main Methods:
- Screened FDA-approved drugs via molecular docking against ILK using the ZINC15 database.
- Validated direct ILK binding of top candidates (nilotinib, teniposide) using surface plasmon resonance (SPR).
- Assessed cytotoxicity and anti-proliferative effects of nilotinib and teniposide in ESCC cell lines via CCK-8 and LDH assays.
Main Results:
- Nilotinib and teniposide demonstrated strong binding affinity to ILK, with KD values lower than the positive control ILK-IN-3.
- Nilotinib (IC50: 40 μM) and teniposide (IC50: 200-400 nM) significantly inhibited ESCC cell proliferation.
- Both drugs significantly suppressed ESCC cell death, as indicated by LDH assay results.
Conclusions:
- Drug repurposing is an effective method for discovering new therapeutic agents for ESCC.
- Nilotinib and teniposide are potent ILK inhibitors with potential for managing ESCC by targeting ILK-mediated signaling pathways.
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