biostudies-literatureUnknownDamghani TNCATS NIH HHSNIGMS NIH HHSInhibitors 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.ACS medicinal chemistry lettershttps://www.ebi.ac.uk/biostudies/studies/S-EPMC12893389biostudies-literatureStructural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.PMC12893389R01 GM143370P30 GM133893UL1 TR001412R01 GM129431R35 GM155353Li JSong SDamghani TLin KSHeppner DEfalseStructural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.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.2026-01-01T00:00:00Z2026 Jan2026-07-15T15:36:31.151Z2026-07-06T03:11:10.729ZS-EPMC128933894168466910.1021/acsmedchemlett.5c00725