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Quinazoline-based fourth-generation EGFR tyrosine kinase inhibitors to overcome C797S-mediated resistance in

Bhatu R Patil1, Kisan Pawara1, Matin Shaikh2

  • 1R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District-, Dhule 425405, Maharashtra, India.

Bioorganic Chemistry
|September 18, 2025
PubMed

Insights

New quinazoline derivatives show promise as fourth-generation EGFR inhibitors. Compound 8d effectively targets triple-mutant EGFR, overcoming Osimertinib resistance in non-small cell lung cancer (NSCLC).

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Biology

Background:

  • Resistance mutations, such as C797S, in epidermal growth factor receptor tyrosine kinase (EGFR-TK) limit Osimertinib efficacy in non-small cell lung cancer (NSCLC).
  • Targeting triple mutant EGFR (L858R/T790M/C797S) is crucial for overcoming acquired resistance.

Purpose of the Study:

  • To design and evaluate novel quinazoline derivatives as potential inhibitors of triple mutant EGFR.
  • To identify potent inhibitors capable of overcoming C797S-mediated resistance in NSCLC.

Main Methods:

  • Synthesis and in vitro evaluation of quinazoline derivatives against triple mutant EGFR.
  • Molecular docking and molecular dynamics (MD) simulations to analyze binding interactions and stability.
  • Structure-activity relationship (SAR) analysis to guide optimization.

Main Results:

  • Compound 8d demonstrated high potency against EGFR L858R/T790M/C797S (IC₅₀ = 0.068 μM), outperforming Osimertinib.
  • Molecular docking revealed interactions with Lys745; MD simulations confirmed ligand stability (RMSD < 2.0 Å, binding free energy -44 kcal/mol).
  • SAR analysis identified key structural features, including a bulky C2 hydrophobic substituent and a sulfonyl group, enhancing potency.

Conclusions:

  • Quinazoline derivatives, exemplified by compound 8d, represent promising fourth-generation EGFR inhibitors.
  • These compounds offer a potential therapeutic strategy to overcome C797S-mediated resistance in NSCLC.
  • Further development of these inhibitors could advance NSCLC treatment paradigms.
Keywords:
EGFR C797S mutationFourth-generation inhibitorsMolecular dockingNon-small cell lung CancerQuinazoline derivatives

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