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

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 EGFR^{L858R/T790M/C797S}. The representative compound <b>C6</b> exhibited a DC₅₀ of 10.2 nM against EGFR^{L858R/T790M/C797S} and an IC₅₀ of 10.3 nM against H1975-TM. Furthermore, <b>C6</b> also showed potent degradation activity against various main EGFR mutants, including EGFR^{Del19/T790M/C797S}. Mechanistic studies revealed that the protein degradation was achieved through the ubiquitin-proteasome system. Finally, <b>C6</b> 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.