1,2,4-Oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Epidermal Growth Factor Receptor (EGFR) and mesenchymal-epithelial transition factor (c-Met) are key oncogenic drivers.
• Targeting these oncoproteins is crucial for cancer therapy, especially in non-small cell lung cancer (NSCLC).
• Developing agents for simultaneous EGFR and c-Met degradation offers a promising therapeutic strategy.

Purpose of the Study:

• To identify novel small molecules that induce simultaneous degradation of EGFR and c-Met.
• To optimize lead compounds for enhanced efficacy and drug-like properties.
• To evaluate the therapeutic potential of the lead compound in preclinical models of NSCLC.

Main Methods:

• High-throughput screening of an in-house library to identify EGFR and c-Met degraders.
• Structure-activity relationship (SAR) studies to optimize lead compounds.
• In vitro assays including antiproliferative activity, cell cycle analysis, Western blotting, and RT-PCR.
• In vivo studies using gefitinib-resistant NSCLC xenograft models in nude mice.

Main Results:

• Compound 1, a 1,2,4-oxadiazole derivative, was identified as a dual EGFR and c-Met suppressor.
• Compound 48, an optimized derivative, demonstrated potent and equipotent antiproliferative activity (IC50 = 0.2-0.6 μM) across diverse NSCLC cell lines.
• Compound 48 induced G2/M cell cycle arrest and apoptosis, downregulated EGFR and c-Met protein levels, and suppressed tumor growth in vivo.
• Compound 48 sensitized gefitinib-resistant tumors to gefitinib treatment.

Conclusions:

• Compound 48 is a highly promising therapeutic candidate for targeting NSCLC, particularly EGFR tyrosine kinase inhibitor (TKI)-resistant forms.
• Dual inhibition and degradation of EGFR and c-Met represent a viable strategy for overcoming drug resistance.
• Further clinical development of compound 48 is warranted for NSCLC treatment.