Design and synthesis of Betti base derivatives as EGFR inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) is a key driver in non-small cell lung cancer (NSCLC).
• Existing EGFR tyrosine kinase inhibitors (TKIs) face challenges with acquired drug resistance.
• Allosteric EGFR inhibitors offer an alternative therapeutic strategy by binding to a different site than ATP-competitive inhibitors.

Purpose of the Study:

• To design and synthesize novel Betti base derivatives as potential allosteric EGFR inhibitors.
• To evaluate the antiproliferative activity and mechanism of action of these derivatives against NSCLC cell lines.
• To investigate the binding mode of the most potent compound within the EGFR allosteric pocket.

Main Methods:

• Structure-based virtual screening to identify initial hit compound ZINC49691377 (1a).
• Design and synthesis of a focused library of Betti base derivatives through substituent modification.
• In vitro antiproliferative assays using NSCLC cell lines (H1975) and Ba/F3 cells with specific EGFR mutations (L858R/T790M/C797S).
• Cell cycle analysis and apoptosis assays.
• Molecular docking and dynamics simulations to predict binding interactions.

Main Results:

• Compound 2b exhibited potent antiproliferative activity against H1975 cells (IC50 = 0.40 ± 0.01 μM) and Ba/F3-EGFR^(L858R/T790M/C797S) cells (IC50 = 2.36 ± 0.33 μM).
• Treatment with 2b induced G0/G1 cell cycle arrest in H1975 cells.
• Compound 2b triggered significant apoptosis in both tested cell lines.
• Molecular modeling confirmed stable binding of 2b within the allosteric pocket of EGFR.

Conclusions:

• Betti base derivatives represent a novel chemotype for developing allosteric EGFR inhibitors.
• Compound 2b demonstrates significant potential as an anticancer agent against EGFR-driven NSCLC, including resistant forms.
• Further development of these Betti base derivatives could lead to new therapeutic options for NSCLC patients.