Abstract
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.