2026-10-10T18:20:37Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34027548 2026-09-29T20:08:05Z category_1 category_4 category_146 category_7 category_19 category_21 category_734 category_931 category_128 category_132 portal_63 item_type_6 month_year_09_2026

Overcoming EGFR Resistance by Monovalent and Bident Inhibitors Targeting Cys775 Zhengnian Li (17888613) Jie Jiang (187037) Yaning Wang (2997282) Scott B. Ficarro (354450) Stephen J. Collins (25138809) Tyler S. Beyett (11586208) Ilse K. Schaeffner (14099860) Isidoro Tavares (12902918) Felix H. Gottlieb (12353994) Dhiraj Suda (25138812) Prafulla C. Gokhale (1937119) Leah M. Black-Holmes (25138815) Dimitris Gazgalis (8958527) Michael J. Eck (240706) Pasi A. Jänne (1277622) Jarrod A. Marto (104616) Jianwei Che (584881) Nathanael S. Gray (150685) Tinghu Zhang (150679) Biophysics Biochemistry Space Science Medicine Pharmacology Biotechnology Biological Sciences not elsewhere classified Information Systems not elsewhere classified Hematology Infectious Diseases resistant mouse models located deep within generation egfr inhibitors egfr covalent inhibitor conventional covalent inhibitors cell lung cancer site mutations ineffective major clinical challenge first intramolecular lock bident compound ynw egfr cysteine 797 overcoming egfr resistance clinical translation causing mutations 797 simultaneously cysteine 775 unprecedented targeting treatment landscape therapeutic potential targeted therapy successful breakthroughs study establishes rendering single fundamentally transforming first evidence first demonstrated enhance resilience currently ongoing covalently targets compelling opportunity c797 remains binding pocket also provides 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. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/acscentsci.6c01219.s001 https://figshare.com/articles/journal_contribution/Overcoming_EGFR_Resistance_by_Monovalent_and_Bident_Inhibitors_Targeting_Cys775/34027548 CC BY-NC 4.0