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Dual Inhibitors of c-MET and EGFR in Triple Negative Breast Cancer: Pharmacophore Modeling and Molecular Dynamics
Shadi Abkhiz1, Parastoo Tarighi1,2, Homa Azizian3
1Department of Medical Biotechnology, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
Background:
The cross-talk between mesenchymal-epithelial transition factor (c-MET) and epidermal growth factor receptor (EGFR) plays a role in breast cancer (BC) progression and resistance to various targeted therapies. Consequently, the simultaneous overexpression of c-MET and EGFR in triple-negative breast cancer (TNBC) is associated with poorer clinicopathological outcomes and increased risks. Despite the development of new c-MET and EGFR inhibitors, the high cost of these drugs makes them inaccessible to most patients.
Objectives:
Our study investigated the therapeutic potential of existing drugs by repurposing small molecules against these two receptors.
Methods:
A database of 2028 small molecule agents was screened using pharmacophore-based virtual screening protocols. To rank the compounds, Gibbs free binding energies were used to analyze their binding energies and interactions with these two receptors.
Results:
It was determined that ARR-4 and ADHHRRR-1 represented the most validated pharmacophore models for c-MET and EGFR, respectively, using receiver operating characteristic (ROC), enrichment factor (EF)1%, and Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC) scores. As a result, eight small molecules were proposed as potential dual inhibitors of c-MET and EGFR, with pasireotide showing the highest affinity for both. According to our analysis of molecular dynamic simulations, pasireotide, the most energetically favorable compound, is proposed as a dual inhibitor of c-MET and EGFR.
Conclusions:
Considering pasireotide's potential to target c-MET and EGFR pathways, our findings provide a strong rationale for its further preclinical validation in the treatment of TNBC. The demonstrated efficacy and safety of pasireotide in this aggressive subtype of cancer can now be evaluated through subsequent studies.
Insights
This study repurposed existing drugs to find new treatments for triple-negative breast cancer (TNBC). Pasireotide emerged as a promising dual inhibitor of c-MET and EGFR, offering a potential low-cost therapy for TNBC.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- The cross-talk between mesenchymal-epithelial transition factor (c-MET) and epidermal growth factor receptor (EGFR) drives breast cancer progression and treatment resistance.
- Simultaneous c-MET and EGFR overexpression in triple-negative breast cancer (TNBC) correlates with poor outcomes.
- Existing targeted therapies for c-MET and EGFR are often prohibitively expensive.
Purpose of the Study:
- To identify existing small molecules with therapeutic potential against both c-MET and EGFR.
- To repurpose affordable drugs for the treatment of triple-negative breast cancer.
- To investigate novel therapeutic strategies for overcoming resistance in breast cancer.
Main Methods:
- Screened a database of 2028 small molecules using pharmacophore-based virtual screening.
- Analyzed binding energies and interactions with c-MET and EGFR using Gibbs free binding energies.
- Validated pharmacophore models using ROC, EF1%, and BEDROC scores, followed by molecular dynamic simulations.
Main Results:
- Identified eight small molecules as potential dual inhibitors of c-MET and EGFR.
- Pasireotide demonstrated the highest binding affinity for both c-MET and EGFR.
- Molecular dynamic simulations confirmed pasireotide as the most energetically favorable dual inhibitor.
Conclusions:
- Pasireotide shows significant potential as a dual inhibitor of c-MET and EGFR for TNBC treatment.
- Further preclinical validation of pasireotide is warranted for its efficacy and safety in TNBC.
- This study provides a strong rationale for repurposing pasireotide as a cost-effective targeted therapy.
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