2. Academic Validation
  3. Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-171884
    EGFR Inhibitor