Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation

The
epidermal growth factor receptor (EGFR) tertiary
C797S mutation
is an important cause of resistance to Osimertinib, which seriously
hinders the clinical application of Osimertinib. Developing proteolysis-targeting
chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy
to overcome drug resistance. In this study, some novel PROTACs targeting
C797S mutation were designed and synthesized based on a new EGFR inhibitor
and displayed a potent degradation effect in H1975-TM cells harboring
EGFRL858R/T790M/C797S. The representative compound C6 exhibited a DC50 of 10.2 nM against EGFRL858R/T790M/C797S and an IC50 of 10.3 nM against
H1975-TM. Furthermore, C6 also showed potent degradation
activity against various main EGFR mutants, including EGFRDel19/T790M/C797S. Mechanistic studies revealed that the protein degradation was achieved
through the ubiquitin–proteasome system. Finally, C6 inhibited tumor growth in the H1975-TM xenograft tumor model effectively
and safely. This study identifies a novel and potent EGFR PROTAC to
overcome Osimertinib resistance mediated by C797S mutation.