CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

Mol Cancer Ther. 2020 Nov;19(11):2288-2297. doi: 10.1158/1535-7163.MCT-20-0229. Epub 2020 Sep 17.


Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (e.g., EAI-045) that potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (e.g., L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, and L858R) over wild type. Furthermore, crystal structure analysis suggested that CH7233163 is a noncovalent ATP-competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib-resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology*
  • Alleles
  • Amino Acid Substitution
  • Aniline Compounds / pharmacology*
  • Animals
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Expression Profiling
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Mutation*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Sequence Deletion
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays


  • Acrylamides
  • Aniline Compounds
  • Protein Kinase Inhibitors
  • osimertinib
  • EGFR protein, human
  • ErbB Receptors