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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Osimertinib is an EGFR-tyrosine kinase inhibitor (TKI) effective against EGFR-T790M-mutated NSCLC.
• Emerging resistance to osimertinib involves EGFR triple mutations, including Del19/T790M/C797S and L858R/T790M/C797S.
• While some allosteric EGFR TKIs target L858R/T790M/C797S, no effective inhibitors exist for Del19/T790M/C797S.

Purpose of the Study:

• To identify a novel therapeutic agent effective against EGFR-Del19/T790M/C797S mutations in NSCLC.
• To evaluate the antitumor activity and selectivity of the identified compound against various EGFR mutations.

Main Methods:

• Identification and characterization of CH7233163 as a potential inhibitor.
• In vitro and in vivo assessment of CH7233163's antitumor activity.
• Crystal structure analysis to elucidate the inhibitory mechanism of CH7233163.

Main Results:

• CH7233163 demonstrated potent antitumor activity against EGFR-Del19/T790M/C797S mutations in vitro and in vivo.
• CH7233163 selectively inhibited various EGFR mutants (including L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, and L858R) over wild-type EGFR.
• Crystal structure analysis revealed CH7233163 as a noncovalent ATP-competitive inhibitor with high affinity for the EGFR's αC-helix-in conformation.

Conclusions:

• CH7233163 is a promising therapeutic candidate for osimertinib-resistant NSCLC, particularly for cases with EGFR-Del19/T790M/C797S mutations.
• The compound's potent activity and selectivity offer a potential new treatment strategy for patients with limited therapeutic options.