biostudies-literatureUnknown65(14)Eno MSWhile epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound <b>30</b>) is a potent, reversible, wild-type-sparing inhibitor of Journal of medicinal chemistry9662-9677https://www.ebi.ac.uk/biostudies/studies/S-EPMC9340769biostudies-literatureDiscovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.PMC9340769Campbell JETimsit YWilson KKim JGuzi TJLee CSchalm SSingh JDe Savi CBrooijmans NStevison FHsieh JOzen APerola EWilliams BDFetalvero KKinkema CGarner AWilson DAlbayya FZhang ZZalutskaya AMedendorp CDineen TABrown VBrubaker JDEno MSWoessner RfalseDiscovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound <b>30</b>) is a potent, reversible, wild-type-sparing inhibitor of 2022-01-01T00:00:00Z2022 Jul2026-05-09T15:35:49.544Z2025-04-06T09:22:25.313ZS-EPMC93407693583876010.1021/acs.jmedchem.2c00704