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Updated: Oct 2, 2025
Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
Multi-targeted Drug Repurposing Approach for Breast Cancer via Integrated Functional Network Analysis
Thirukumaran Kandasamy1, Plaboni Sen1, Siddhartha Sankar Ghosh1,2
1Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 39, Assam, India.
Abstract:
The present study focuses on the interconnected functional network of altered metabolism and EMT (epithelial to mesenchymal transition) signaling in breast cancer. We have interlinked the metabolic and EMT signaling circuits and selected Insulin receptor (IR), Integrin beta 1 (ITGB1), and CD36 as target proteins based on network analysis. Extensive computational approaches discerned the potential drug molecules from the library of 1293 FDA-approved drugs to block all three target proteins. Using molecular docking, molecular dynamics simulation, and MMPBSA binding free energy studies, Capmatinib, Ponatinib, Naldemedine, and Pimozide were identified as potential repurposed drugs to block the function of all three target proteins. Among in silico selected candidate drugs, Pimozide, a known anti-psychotic drug, was further validated using in-vitro studies for its anti-cell proliferative potential on breast cancer cell lines (namely, MCF7, MDAMB231 and MDAMB468). The inhibitory concentration (IC50 ) values of MCF7, MDAMB231 and MDAMB468 was found to be 16.26 μM, 20.82 μM and 13.10 μM, respectively. The effect of Pimozide on EMT-induced MDAMB231 and MDAMB468 cells was evident from their IC50 values of 7.85 μM and 6.83 μM, respectively. The potent anti-cancer property of Pimozide has opened up avenues for drug repurposing towards 'multi-targeted therapy' in EMT dynamics.
Insights
This study identifies Pimozide as a potential repurposed drug for breast cancer treatment. It effectively inhibits cancer cell proliferation and epithelial to mesenchymal transition (EMT) by targeting key metabolic and EMT signaling proteins.
Area of Science:
- Oncology
- Computational Biology
- Pharmacology
Background:
- Altered metabolism and epithelial to mesenchymal transition (EMT) signaling are critical in breast cancer progression.
- Interconnecting these pathways reveals a functional network driving cancer development.
Purpose of the Study:
- To identify FDA-approved drugs for repurposing against breast cancer by targeting key proteins in the metabolic and EMT signaling network.
- To computationally screen a library of drugs and validate promising candidates in vitro.
Main Methods:
- Network analysis to identify target proteins: Insulin receptor (IR), Integrin beta 1 (ITGB1), and CD36.
- Computational drug screening of 1293 FDA-approved drugs using molecular docking, simulation, and binding free energy calculations.
- In vitro validation of identified drugs, focusing on Pimozide's anti-proliferative and anti-EMT effects on breast cancer cell lines.
Main Results:
- Pimozide, Capmatinib, Ponatinib, and Naldemedine were identified as potential drugs targeting all three proteins.
- Pimozide demonstrated significant anti-proliferative activity against MCF7, MDAMB231, and MDAMB468 cell lines.
- Pimozide effectively inhibited EMT in MDAMB231 and MDAMB468 cells at low IC50 values.
Conclusions:
- Pimozide exhibits potent anti-cancer properties, suggesting its potential for drug repurposing in breast cancer.
- Targeting the interconnected metabolic and EMT signaling network offers a promising multi-targeted therapy approach.
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