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

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

Kenji Kashima  1 , Hiroki Kawauchi  2 , Hiromi Tanimura  2 , Yukako Tachibana  2 , Takashi Chiba  2 , Takuya Torizawa  2 , Hiroshi Sakamoto  2
Affiliations

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

Kenji Kashima et al. Mol Cancer Ther. 2020 Nov.

Abstract

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.

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