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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The C797S mutation in epidermal growth factor receptor (EGFR) confers resistance to Osimertinib, limiting its clinical efficacy.
• Proteolysis-targeting chimeras (PROTACs) represent a promising therapeutic strategy to overcome drug resistance by inducing protein degradation.

Purpose of the Study:

• To design and synthesize novel PROTACs targeting EGFR mutants, specifically addressing Osimertinib resistance mediated by the C797S mutation.
• To evaluate the efficacy of these PROTACs in degrading EGFR mutants and inhibiting tumor growth.

Main Methods:

• Design and synthesis of novel PROTACs based on a new EGFR inhibitor.
• Assessment of PROTACs' degradation efficacy against EGFR mutants (e.g., EGFR^{L858R/T790M/C797S}) in cancer cell lines (H1975-TM).
• In vivo studies using a xenograft tumor model to evaluate anti-tumor activity and safety.

Main Results:

• The representative compound C6 demonstrated potent degradation of EGFR^{L858R/T790M/C797S} (DC50 = 10.2 nM) and EGFR^{Del19/T790M/C797S}.
• Compound C6 exhibited significant anti-tumor efficacy in the H1975-TM xenograft model.
• Mechanistic studies confirmed degradation via the ubiquitin-proteasome system.

Conclusions:

• Novel PROTACs, exemplified by C6, effectively overcome Osimertinib resistance driven by EGFR C797S mutations.
• These PROTACs offer a potential new therapeutic avenue for patients with resistant EGFR-mutated non-small cell lung cancer.