Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting
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.
Fields of Study & Subjects
Lung Cancer Treatments and Mutations
Colorectal Cancer Treatments and Studies
Cancer therapeutics and mechanisms
Publication details
- Journal / source
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Volume
- 17
- Issue
- 2
- Pages
- 531–537
- Publication date
- 15 January 2026
- Language
- EN