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Multi-Targeting Approach in Glioblastoma Using Computer-Assisted Drug Discovery Tools to Overcome the Blood-Brain
Catarina Franco1,2, Samina Kausar1,2, Margarida F B Silva2,3
1LASIGE, Department of Informatics, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
Abstract:
The epidermal growth factor receptor (EGFR) is upregulated in glioblastoma, becoming an attractive therapeutic target. However, activation of compensatory pathways generates inputs to downstream PI3Kp110β signaling, leading to anti-EGFR therapeutic resistance. Moreover, the blood-brain barrier (BBB) limits drugs' brain penetration. We aimed to discover EGFR/PI3Kp110β pathway inhibitors for a multi-targeting approach, with favorable ADMET and BBB-permeant properties. We used quantitative structure-activity relationship models and structure-based virtual screening, and assessed ADMET properties, to identify BBB-permeant drug candidates. Predictions were validated in in vitro models of the human BBB and BBB-glioma co-cultures. The results disclosed 27 molecules (18 EGFR, 6 PI3Kp110β, and 3 dual inhibitors) for biological validation, performed in two glioblastoma cell lines (U87MG and U87MG overexpressing EGFR). Six molecules (two EGFR, two PI3Kp110β, and two dual inhibitors) decreased cell viability by 40-99%, with the greatest effect observed for the dual inhibitors. The glioma cytotoxicity was confirmed by analysis of targets' downregulation and increased apoptosis (15-85%). Safety to BBB endothelial cells was confirmed for three of those molecules (one EGFR and two PI3Kp110β inhibitors). These molecules crossed the endothelial monolayer in the BBB in vitro model and in the BBB-glioblastoma co-culture system. These results revealed novel drug candidates for glioblastoma treatment.
Insights
Researchers identified novel drug candidates targeting both epidermal growth factor receptor (EGFR) and PI3Kp110β pathways to overcome glioblastoma resistance and blood-brain barrier challenges. These dual inhibitors show promising efficacy and safety for treating brain tumors.
Area of Science:
- Oncology
- Pharmacology
- Neuroscience
Background:
- Glioblastoma exhibits upregulated epidermal growth factor receptor (EGFR), a key therapeutic target.
- Compensatory signaling pathways and the blood-brain barrier (BBB) contribute to therapeutic resistance and limit drug efficacy.
- Targeting both EGFR and PI3Kp110β simultaneously offers a potential strategy to overcome resistance.
Purpose of the Study:
- To discover novel inhibitors of the EGFR/PI3Kp110β pathway with favorable ADMET properties and BBB permeability.
- To develop multi-targeting agents for glioblastoma treatment, addressing resistance mechanisms.
- To validate potential drug candidates using in vitro models of the BBB and glioblastoma.
Main Methods:
- Quantitative structure-activity relationship (QSAR) modeling and structure-based virtual screening were employed.
- ADMET properties and BBB permeability were assessed computationally.
- In vitro validation involved human BBB models, BBB-glioma co-cultures, and glioblastoma cell lines (U87MG).
Main Results:
- 27 potential inhibitors were identified (18 EGFR, 6 PI3Kp110β, 3 dual inhibitors).
- Six molecules demonstrated significant glioblastoma cell viability reduction (40-99%), with dual inhibitors showing the greatest effect.
- Three molecules (one EGFR, two PI3Kp110β) showed safety for BBB endothelial cells and successfully crossed the BBB in vitro.
Conclusions:
- Novel drug candidates targeting EGFR and PI3Kp110β pathways were discovered.
- Dual inhibitors exhibit potent anti-glioma activity and potential for BBB penetration.
- These findings present promising therapeutic options for glioblastoma treatment, overcoming resistance and BBB limitations.
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