Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Computational Chemistry

Background:

• Drug resistance in non-small cell lung cancer (NSCLC) is a major challenge, particularly mutations in the epidermal growth factor receptor (EGFR).
• Developing next-generation EGFR tyrosine kinase inhibitors (TKIs) is crucial to overcome resistance mediated by EGFR mutations like L858R/T790M and L858R/T790M/C797S.

Purpose of the Study:

• To discover novel EGFR tyrosine kinase inhibitors (TKIs) with potent activity against resistant EGFR mutations.
• To evaluate the EGFR inhibitory and antiproliferative activities of a series of furopyridine derivatives.

Main Methods:

• Virtual screening using molecular docking and solvated interaction energy (SIE) methods.
• In vitro enzymatic assays to determine inhibitory activity (IC50) against wild-type and mutant EGFR.
• Cell-based assays to assess antiproliferative effects on NSCLC cell lines.
• Molecular dynamics (MD) simulations to elucidate binding mechanisms.

Main Results:

• Several furopyridine derivatives demonstrated potential to inhibit wild-type and mutant EGFR.
• The compound PD13 exhibited strong inhibitory activity against wild-type (IC50: 11.64 ± 1.30 nM) and L858R/T790M (IC50: 10.51 ± 0.71 nM) EGFR, surpassing known drugs.
• PD13 showed potent cytotoxic effects on A549 and H1975 NSCLC cell lines (IC50: 18.09 ± 1.57 µM and 33.87 ± 0.86 µM, respectively).
• MD simulations revealed that PD13 forms stabilizing hydrogen bonds with Met793 in the EGFR hinge region.

Conclusions:

• PD13 is a promising novel EGFR inhibitor with significant activity against resistant mutations.
• The binding interaction in the EGFR hinge region is key to PD13's inhibitory activity.
• PD13 warrants further clinical development as a potential fourth-generation EGFR-TKI for NSCLC treatment.