Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting

  • ACS Med Chem Lett. 2026 Jan 15:10.1021/acsmedchemlett.5c00725. doi: 10.1021/acsmedchemlett.5c00725.
Tahereh Damghani  1 ,  Shenghan Song  2 ,  Kaly S Lin  1 ,  Jianing Li  2 ,  David E Heppner  1  3  4  5
Affiliations
  • 1. Department of Chemistry, College of Arts and Sciences, The State University of New York at Buffalo, Buffalo, New York 14260, United States.
  • 2. Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
  • 3. Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York 14203, United States.
  • 4. Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York 14214, United States.
  • 5. Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States.
PMID: 41684669 DOI: 10.1021/acsmedchemlett.5c00725
Abstract

Inhibitors targeting mutant EGFR remain a persistent need in combating drug resistance in non-small cell lung Cancer. To better understand the molecular factors involved in targeting T790M and C797S mutations, we determined X-ray cocrystal structures of fourth-generation inhibitors BI-8128 and BI-4732. Analysis from molecular dynamics and thermodynamic integration calculations correlated with biochemical and cellular measurements indicate that BI-8128 binds the double T790M/C797S more strongly than the single mutations individually. This observation showcases strengths in the design of these fourth-generation EGFR inhibitors as profile criteria require drugs to inhibit an array of oncogenic and drug resistance mutations.

Keywords
EGFR; crystallography; kinase inhibitors; molecular dynamics; non-small cell lung cancer; structural biology; targeted therapy.
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