EGFR Kinase Inhibiting Amino-enones for Breast Cancer; CADD Approach

Area of Science:

• Medicinal Chemistry
• Computational Drug Design
• Oncology

Background:

• Epidermal Growth Factor Receptor (EGFR) kinase is a key target in cancer therapy, particularly for breast cancer.
• EGFR overexpression correlates with genomic instability and aggressive tumor characteristics.
• Computer-Aided Drug Discovery (CADD) is crucial for identifying novel kinase inhibitors.

Purpose of the Study:

• To computationally validate amide-substituted β-amino enones as potential EGFR kinase inhibitors.
• To assess the in vitro anticancer activity of these compounds against breast cancer cell lines.
• To investigate the antioxidant potential of the compounds, considering the role of Reactive Oxygen Species (ROS) in cancer.

Main Methods:

• In silico methods included molecular docking, MD simulations, DFT calculations, and ADMET predictions to establish structure-activity relationships (SAR).
• In vitro studies utilized BT474 (ER+HER2+) and MCF-7 (ER-HER2) breast cancer cell lines and normal MFC-10a cells.
• EGFR kinase inhibition assays and antioxidant potential analyses were performed.

Main Results:

• Eleven amide-substituted (Z)-β-amino enones were synthesized and evaluated.
• Compounds 5b, 5c, 5g, and 5h demonstrated significant in silico and in vitro bioactivity.
• Computational predictions strongly correlated with experimental findings.

Conclusions:

• Compounds 5b, 5c, 5g, and 5h are identified as promising candidates for EGFR kinase inhibition.
• These compounds exhibit notable anticancer properties.
• Further pre-clinical and clinical evaluations are recommended for their development as cancer therapeutics.