Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.

ABSTRACT: Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophob

SUBMITTER: Grabe T 

PROVIDER: S-EPMC10184309 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature