{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Damghani T"],"funding":["NCATS NIH HHS","NIGMS NIH HHS"],"pubmed_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."],"journal":["ACS medicinal chemistry letters"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12893389"],"repository":["biostudies-literature"],"pubmed_title":["Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting."],"pmcid":["PMC12893389"],"funding_grant_id":["R01 GM143370","P30 GM133893","UL1 TR001412","R01 GM129431","R35 GM155353"],"pubmed_authors":["Li J","Song S","Damghani T","Lin KS","Heppner DE"],"additional_accession":[]},"is_claimable":false,"name":"Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.","description":"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.","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Jan","modification":"2026-07-15T15:36:31.151Z","creation":"2026-07-06T03:11:10.729Z"},"accession":"S-EPMC12893389","cross_references":{"pubmed":["41684669"],"doi":["10.1021/acsmedchemlett.5c00725"]}}