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Peer-reviewedCC BYACS central science

Overcoming EGFR Resistance by Monovalent and Bident Inhibitors Targeting Cys775

  • Zhengnian Li1,2
  • Jie Jiang3,4
  • Yaning Wang1,2
  • Scott B. Ficarro5
  • Stephen J. Collins6,7
  • Tyler S. Beyett6,7
  • Ilse K. Schaeffner6,7
  • Isidoro Tavares6,8
  • Felix H. Gottlieb3,4
  • Dhiraj Suda9
  • Prafulla C. Gokhale9
  • Leah M. Black-Holmes3,4
7 more authors
  • Dimitris Gazgalis6,7
  • Michael J. Eck6,7
  • Pasi A. Jänne3,4
  • Jarrod A. Marto5
  • Jianwei Che6
  • Nathanael S. Gray1,2
  • Tinghu Zhang1,2
9 affiliations
  1. 1Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305, United States
  2. 2Stanford Cancer Institute, ChEM-H, Stanford University, Stanford, California 94305, United States
  3. 3Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana−Farber Cancer Institute, Boston, Massachusetts 02215, United States
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States
  5. 5Department of Biochemistry & Molecular Genetics, University of Virginia School of Medicine, Department of Chemistry, University of Virginia College and Graduate School of Arts & Sciences, Charlottesville, Virginia 22904, United States
  6. 6Department of Cancer Biology, Dana−Farber Cancer Institute, Boston, Massachusetts 02215, United States
  7. 7Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
  8. 8Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, United States
  9. 9Experimental Therapeutics Core and Robert and Renée Belfer Center for Applied Cancer Science, Dana−Farber Cancer Institute, Boston, Massachusetts 02215, United States
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Abstract

Covalent targeting of EGFR cysteine 797 by osimertinib is one of the most successful breakthroughs in targeted therapy, fundamentally transforming the treatment landscape for non-small-cell lung cancer (NSCLC) patients. However, resistance driven by the mutation of C797 remains a major clinical challenge. Developing novel covalent strategies beyond C797 targeting presents a compelling opportunity for next-generation EGFR inhibitors. We first demonstrated that cysteine 775, located deep within the ATP-binding pocket, is accessible by a rationally designed covalent molecule ZNL-3, which as the first-in-class covalent cysteine 775 inhibitor exhibited strong efficacy in osimertinib-resistant mouse models. To further enhance resilience to resistance-causing mutations, we developed a dual-warhead, bident compound YNW-1 which covalently targets both cysteines 775 and 797 simultaneously. YNW-1 is the first intramolecular lock to exhibit balanced reactive efficiency on both cysteines, rendering single-site mutations ineffective at conferring resistance. This study establishes the therapeutic potential of an EGFR covalent inhibitor through unprecedented targeting of cysteine 775. It also provides the first evidence that dual-cysteine engagement offers superior efficacy to conventional covalent inhibitors by delaying the emergence of resistance. Further optimization for clinical translation is currently ongoing in our laboratory.

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Cite

BibTeXRIS
BibTeX
@article{li2026overcoming,
  title = {{Overcoming EGFR Resistance by Monovalent and Bident Inhibitors Targeting Cys775}},
  author = {Zhengnian Li and Jie Jiang and Yaning Wang and Scott B. Ficarro and Stephen J. Collins and Tyler S. Beyett and Ilse K. Schaeffner and Isidoro Tavares and Felix H. Gottlieb and Dhiraj Suda and Prafulla C. Gokhale and Leah M. Black-Holmes and Dimitris Gazgalis and Michael J. Eck and Pasi A. Jänne and Jarrod A. Marto and Jianwei Che and Nathanael S. Gray and Tinghu Zhang},
  journal = {ACS central science},
  year = {2026},
  month = sep,
  doi = {10.1021/acscentsci.6c01219},
  url = {https://europepmc.org/article/PMC/PMC13720926},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Overcoming EGFR Resistance by Monovalent and Bident Inhibitors Targeting Cys775
AU  - Zhengnian Li
AU  - Jie Jiang
AU  - Yaning Wang
AU  - Scott B. Ficarro
AU  - Stephen J. Collins
AU  - Tyler S. Beyett
AU  - Ilse K. Schaeffner
AU  - Isidoro Tavares
AU  - Felix H. Gottlieb
AU  - Dhiraj Suda
AU  - Prafulla C. Gokhale
AU  - Leah M. Black-Holmes
AU  - Dimitris Gazgalis
AU  - Michael J. Eck
AU  - Pasi A. Jänne
AU  - Jarrod A. Marto
AU  - Jianwei Che
AU  - Nathanael S. Gray
AU  - Tinghu Zhang
PY  - 2026
DA  - 2026/09/01
JO  - ACS central science
DO  - 10.1021/acscentsci.6c01219
UR  - https://europepmc.org/article/PMC/PMC13720926
AB  - Covalent targeting of EGFR cysteine 797 by osimertinib is one of the most successful breakthroughs in targeted therapy, fundamentally transforming the treatment landscape for non-small-cell lung cancer (NSCLC) patients. However, resistance driven by the mutation of C797 remains a major clinical challenge. Developing novel covalent strategies beyond C797 targeting presents a compelling opportunity for next-generation EGFR inhibitors. We first demonstrated that cysteine 775, located deep within the ATP-binding pocket, is accessible by a rationally designed covalent molecule ZNL-3, which as the first-in-class covalent cysteine 775 inhibitor exhibited strong efficacy in osimertinib-resistant mouse models. To further enhance resilience to resistance-causing mutations, we developed a dual-warhead, bident compound YNW-1 which covalently targets both cysteines 775 and 797 simultaneously. YNW-1 is the first intramolecular lock to exhibit balanced reactive efficiency on both cysteines, rendering single-site mutations ineffective at conferring resistance. This study establishes the therapeutic potential of an EGFR covalent inhibitor through unprecedented targeting of cysteine 775. It also provides the first evidence that dual-cysteine engagement offers superior efficacy to conventional covalent inhibitors by delaying the emergence of resistance. Further optimization for clinical translation is currently ongoing in our laboratory.
SN  - 2374-7943
SN  - 2374-7951
ER  -