Work

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

Year: 2026

Type: article

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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00725

Authors: Tahereh Damghani, Shenghan Song, Kaly S. Lin, Jianing Li, David E. Heppner

Institutions: University at Buffalo, State University of New York, Purdue University West Lafayette, Roswell Park Comprehensive Cancer Center

Language: English

Topic: Lung Cancer Treatments and Mutations

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institute of General Medical Sciences, National Center for Advancing Translational Sciences, Biological and Environmental Research