Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Epidermal growth factor receptor (EGFR) overexpression/mutation drives solid tumor growth.
• Resistance to current EGFR-targeting therapies necessitates novel therapeutic strategies.
• A newly identified prone extracellular tetrameric EGFR configuration presents a potential drug target.

Purpose of the Study:

• To computationally target and stabilize the novel prone EGFR tetramer using small molecule ligands.
• To identify and evaluate compounds that modulate the function of this specific EGFR conformation.

Main Methods:

• Virtual screening of over 345,000 compounds against a molecular dynamics simulation of the EGFR tetramer.
• Cell-based high-content imaging to assess Grb2 internalization upon EGFR activation.
• Evaluation of hit compounds for effects on EGFR and ERK1/2 phosphorylation.

Main Results:

• Fourteen compounds demonstrated an effect on Grb2 internalization, an indicator of EGFR pathway modulation.
• Most identified compounds showed minimal impact on cell viability and EGFR/ERK1/2 phosphorylation.
• Docking analysis revealed interactions with key residues, including Arg270, relevant to existing EGFR therapies.

Conclusions:

• The study validates the prone EGFR tetrameric configuration as a novel target for cancer drug development.
• These findings provide a foundation for further chemical optimization of identified hit compounds.