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Updated: Jan 22, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Repurposing drugs for EGFR-targeted cancer therapy: An in silico and in vitro study with pharmacophore-based insights
Pınar Siyah1, Firat Baris Barlas2
1Department of Biochemistry, School of Pharmacy, Bahcesehir University, 34500, Istanbul, Türkiye.
Abstract:
Cancer is the second leading cause of death globally and remains a priority due to its impact on life quality, treatment complexity, and high costs. To expedite drug development, researchers are increasingly repurposing FDA-approved drugs and clinical candidates, reducing time and costs through in silico methods. In this study, 3235 FDA-approved and clinical molecules were screened for EGFR inhibition, a significant target due to its role in cancer progression and treatment resistance. A pharmacophore model was generated based on erlotinib's co-crystallized structure and quantitative structure-activity relationships. Molecules meeting the pharmacophoric criteria underwent SP and XP docking, with thresholds of -6.00 kcal/mol and -7.00 kcal/mol, respectively, followed by anti-cancer potential analysis via MetaCore/MetaDrug and MD simulations at 1, 10, and 100 ns to assess EGFR-binding stability. For the molecule Ticagrelor, which demonstrated particularly promising results, and Erlotinib cell culture viability assays were conducted across three cell lines-cancerous A549, U87, and healthy BEAS-2B- (IC50) of, 8.2576 μM, 9.4058 μM, and 15.893 μM, respectively for Ticagrelor and 11.708 μM, 12.747 μM and 14.6709 μM, respectively for Erlotinib. In silico results highlight Ticagrelor's significant EGFR-inhibiting potential with enhanced binding stability compared to the reference.
Insights
Researchers screened drugs for EGFR inhibition, a key cancer target. Ticagrelor showed significant potential, demonstrating enhanced binding stability and anti-cancer activity in cell assays compared to erlotinib.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Cancer is a leading global cause of death, necessitating novel therapeutic strategies.
- Drug repurposing offers an accelerated approach to cancer drug development.
- Epidermal Growth Factor Receptor (EGFR) is a critical target in cancer progression and treatment resistance.
Purpose of the Study:
- To identify novel EGFR inhibitors through in silico screening of FDA-approved and clinical molecules.
- To evaluate the binding stability and anti-cancer potential of identified inhibitors.
Main Methods:
- Generation of a pharmacophore model based on erlotinib and quantitative structure-activity relationships.
- Screening of 3235 molecules for EGFR inhibition using pharmacophore matching, SP, and XP docking.
- Analysis of anti-cancer potential using MetaCore/MetaDrug and molecular dynamics (MD) simulations.
- Cell viability assays (IC50) on A549, U87, and BEAS-2B cell lines for Ticagrelor and Erlotinib.
Main Results:
- Ticagrelor exhibited significant EGFR-inhibiting potential.
- Molecular dynamics simulations indicated enhanced binding stability for Ticagrelor compared to erlotinib.
- Cell viability assays confirmed anti-cancer activity: Ticagrelor IC50 values were 8.26 μM (A549), 9.41 μM (U87), and 15.89 μM (BEAS-2B); Erlotinib IC50 values were 11.71 μM (A549), 12.75 μM (U87), and 14.67 μM (BEAS-2B).
Conclusions:
- In silico screening identified Ticagrelor as a promising candidate for EGFR-targeted cancer therapy.
- Ticagrelor demonstrates superior binding stability and comparable or improved anti-cancer efficacy over erlotinib.
- Further investigation of Ticagrelor as an anti-cancer agent is warranted.
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