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<p>Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a major therapeutic challenge in EGFR-mutant cancers. While third-generation covalent EGFR inhibitors successfully suppress the T790M-mediated resistance, acquisition of the C797S substitution abrogates irreversible drug binding and represents a dominant mechanism of therapeutic failure. To address this challenge, we implemented a structure-guided discovery framework to identify reversible, ATP-competitive EGFR inhibitors capable of targeting C797S-containing mutants. We integrated virtual screening, molecular docking, and molecular dynamics–based prioritization with experimental validation in engineered Ba/F3 models expressing clinically relevant EGFR resistance genotypes. Several lead candidates demonstrated potent inhibition of C797S-mutant EGFR signaling in vitro, with potencies comparable to those reported for clinically advanced fourth-generation EGFR inhibitors. In an EGFR T790M/C797S/L858R xenograft model, oral administration of the reversible inhibitor BLU-945 produced significant tumor growth inhibition, confirming the in vivo tractability of C797S-driven EGFR signaling. In contrast, the structurally related tool compound F471-0411 exhibited limited antitumor efficacy following intratumoral delivery, suggesting that pharmacokinetic or exposure constraints, rather than lack of intrinsic cellular activity likely limited its in vivo potency. Collectively, these findings highlight the utility of structure-guided screening for identifying novel EGFR C797S–active scaffolds and provide translational insights to inform the design of next-generation EGFR inhibitors.</p>

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Structure-guided identification and biological evaluation of reversible EGFR C797S inhibitors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Glen J. Weiss,
  • Joseph C. Loftus,
  • David W. Mallery,
  • Nhan L. Tran

摘要

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a major therapeutic challenge in EGFR-mutant cancers. While third-generation covalent EGFR inhibitors successfully suppress the T790M-mediated resistance, acquisition of the C797S substitution abrogates irreversible drug binding and represents a dominant mechanism of therapeutic failure. To address this challenge, we implemented a structure-guided discovery framework to identify reversible, ATP-competitive EGFR inhibitors capable of targeting C797S-containing mutants. We integrated virtual screening, molecular docking, and molecular dynamics–based prioritization with experimental validation in engineered Ba/F3 models expressing clinically relevant EGFR resistance genotypes. Several lead candidates demonstrated potent inhibition of C797S-mutant EGFR signaling in vitro, with potencies comparable to those reported for clinically advanced fourth-generation EGFR inhibitors. In an EGFR T790M/C797S/L858R xenograft model, oral administration of the reversible inhibitor BLU-945 produced significant tumor growth inhibition, confirming the in vivo tractability of C797S-driven EGFR signaling. In contrast, the structurally related tool compound F471-0411 exhibited limited antitumor efficacy following intratumoral delivery, suggesting that pharmacokinetic or exposure constraints, rather than lack of intrinsic cellular activity likely limited its in vivo potency. Collectively, these findings highlight the utility of structure-guided screening for identifying novel EGFR C797S–active scaffolds and provide translational insights to inform the design of next-generation EGFR inhibitors.