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Updated: Jan 24, 2026

Production and Targeting of Monovalent Quantum Dots
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Production and Targeting of Monovalent Quantum Dots

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Overcoming EGFR resistance by monovalent and bident inhibitors targeting Cys775

Zhengnian Li, Jie Jiang, Yaning Wang

    Biorxiv : the Preprint Server for Biology
    |January 23, 2026
    PubMed

    Insights

    New covalent inhibitors targeting cysteine 775 and dual cysteine 775/797 engagement offer potent strategies against non-small cell lung cancer (NSCLC) with EGFR mutations, overcoming osimertinib resistance.

    Area of Science:

    • Oncology
    • Medicinal Chemistry
    • Molecular Biology

    Background:

    • Osimertinib's covalent targeting of EGFR cysteine 797 revolutionized non-small cell lung cancer (NSCLC) treatment.
    • Resistance mutations, particularly at C797, pose a significant clinical challenge, necessitating next-generation inhibitors.

    Purpose of the Study:

    • To develop novel covalent strategies targeting alternative sites on EGFR to overcome osimertinib resistance.
    • To investigate the efficacy of targeting cysteine 775 and dual targeting of cysteines 775 and 797.

    Main Methods:

    • Rational design and synthesis of covalent molecules targeting specific EGFR cysteine residues.
    • In vitro and in vivo evaluation of novel inhibitors (ZNL-3 and YNW-1) in osimertinib-resistant NSCLC models.

    Main Results:

    • ZNL-3, a first-in-class covalent inhibitor of EGFR cysteine 775, demonstrated efficacy in osimertinib-resistant models.
    • YNW-1, a dual-warhead compound, simultaneously targets both cysteine 775 and 797, showing enhanced resilience to resistance mutations.
    • YNW-1 exhibits balanced reactivity, rendering single-site mutations ineffective for resistance development.

    Conclusions:

    • Targeting EGFR cysteine 775 represents a viable therapeutic strategy for overcoming osimertinib resistance in NSCLC.
    • Dual covalent targeting of EGFR cysteines 775 and 797 offers superior efficacy and resistance-delaying properties compared to conventional single-site covalent inhibitors.
    • Further optimization of ZNL-3 and YNW-1 holds promise for clinical translation in EGFR-mutated NSCLC.

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