Design, Synthesis, and Anticancer Evaluation of New Small-Molecule EGFR Inhibitors Targeting NSCLC and Breast Cancer

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Epidermal Growth Factor Receptor (EGFR) is a key driver in non-small-cell lung cancer (NSCLC) and is overexpressed in breast cancer.
• Targeting EGFR is a significant strategy for cancer therapy.
• Developing novel EGFR inhibitors with potent anticancer activity is crucial.

Purpose of the Study:

• To synthesize and evaluate new compounds as potential EGFR inhibitors and anticancer agents.
• To assess the cytotoxicity and apoptosis-inducing effects of novel compounds on NSCLC and breast cancer cells.
• To investigate the EGFR inhibitory activity and in silico pharmacokinetic properties of the most potent compounds.

Main Methods:

• Synthesis of 18 novel compounds.
• Cytotoxicity assays using A549 (NSCLC), MCF-7 (breast cancer), Jurkat cells, and PBMCs.
• Apoptosis induction assays.
• EGFR inhibitory activity assessment.
• Molecular docking at the EGFR ATP-binding site.
• In silico prediction of pharmacokinetic and toxicity parameters.

Main Results:

• Compound B-2 exhibited the highest cytotoxicity against A549 (IC50 = 2.14 μM) and MCF-7 (IC50 = 8.91 μM) cells.
• B-2 demonstrated selective cytotoxicity against cancer cells over healthy PBMCs (SI = 23.2).
• B-2 induced apoptosis in A549 and MCF-7 cells and showed significant EGFR inhibition (66% at 10 μM) with strong binding affinity.
• In silico analysis indicated favorable drug-like properties and no predicted carcinogenic, genotoxic, or mutagenic effects for B-2.

Conclusions:

• Compound B-2 is a potent EGFR inhibitor and apoptosis inducer with selective cytotoxicity.
• B-2 shows significant promise as a lead compound for developing novel therapies against NSCLC and breast cancer.
• Further research into B-2 is warranted for its potential clinical application in oncology.