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Accelerating Scaffold Hopping in Fourth-Generation Epidermal Growth Factor Receptor Inhibitors via Multilevel Virtual

Zhiqi Sun1, Donghui Huo1, Jiangyu Guo1

  • 1State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, P.O. Box 53, 15 BeiSanHuan East Road, Beijing 100029, P. R. China.

ACS Medicinal Chemistry Letters
|October 15, 2025
PubMed
Summary
This summary is machine-generated.

This study developed a novel virtual screening method to find inhibitors for drug-resistant epidermal growth factor receptor (EGFR) mutations. Compound L15 effectively inhibits L858R/T790M/C797S mutant EGFR, offering a new strategy against cancer drug resistance.

Keywords:
L858R/T790M/C797S mutant EGFRepidermal growth factor receptor (EGFR)molecular dynamics simulationmultitask deep learningvirtual screening

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Epidermal growth factor receptor (EGFR) signaling is vital for cell functions, but drug resistance, particularly via mutations like L858R/T790M/C797S, limits treatment efficacy.
  • Developing novel inhibitors is crucial to overcome acquired resistance in EGFR-targeted therapies.

Purpose of the Study:

  • To establish a systematic multilevel virtual screening strategy to identify inhibitors targeting drug-resistant EGFR mutations.
  • To discover novel inhibitors effective against the L858R/T790M/C797S and d746-750/T790M/C797S EGFR variants.

Main Methods:

  • Integrated 3D shape similarity screening, deep learning-based activity prediction, molecular docking, and molecular dynamics simulations.
  • Screened 18 million drug-like molecules, followed by in vitro enzymatic testing of 12 candidates.
  • Utilized free energy decomposition to analyze molecular interactions.

Main Results:

  • Identified three novel scaffold inhibitors, with Compound L15 showing potent activity against L858R/T790M/C797S mutant EGFR (IC50 = 16.43 nM).
  • Compound L15 demonstrated 5-fold selectivity over wild-type EGFR and comparable efficacy against the d746-750/T790M/C797S variant.
  • L15 binding is stabilized by hydrophobic interactions with LEU718 and LEU792.

Conclusions:

  • The developed multilevel virtual screening strategy is effective for overcoming EGFR resistance.
  • Compound L15 represents a promising lead for developing fourth-generation EGFR inhibitors.
  • Structural and mechanistic insights are provided for rational drug design against resistant EGFR mutations.