Discovering potent EGFR inhibitors through the structural optimization of the Betti-base scaffold

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).
• The C797S mutation confers resistance to existing EGFR inhibitors, necessitating new therapeutic strategies.
• Allosteric inhibitors offer a promising alternative by targeting distinct binding sites.

Purpose of the Study:

• To optimize the Betti-base scaffold for EGFR inhibition, focusing on overcoming C797S resistance.
• To evaluate the anti-proliferative and mechanistic effects of novel Betti-base derivatives.
• To provide a structural basis for the efficacy of lead compounds through computational modeling.

Main Methods:

• Synthesis and optimization of Betti-base derivatives with hydrophilic groups.
• In vitro anti-proliferative assays using NSCLC cell lines (H1975 and Ba/F3-EGFR).
• Western blotting to assess EGFR phosphorylation and apoptosis assays.
• Molecular docking and dynamics simulations to elucidate binding modes.

Main Results:

• Compound 2b demonstrated potent anti-proliferative activity against EGFR-mutated cell lines, including those with the C797S mutation.
• IC50 values for compound 2b were comparable to the positive control JBJ-04-125-02.
• 2b effectively suppressed EGFR phosphorylation and induced apoptosis in a dose-dependent manner.
• Molecular simulations confirmed stable binding of 2b to the EGFR allosteric site.

Conclusions:

• Compound 2b is a highly promising lead compound for developing new therapies against NSCLC harboring the C797S resistance mutation.
• The optimized Betti-base scaffold represents a novel chemotype for EGFR allosteric inhibitors.
• Further development of 2b could address a critical unmet need in NSCLC treatment.