Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Acquired resistance to third-generation EGFR inhibitors in cancer is often driven by the EGFR C797S mutation.
• Existing small-molecule inhibitors targeting EGFR C797S can lead to new resistance mutations.
• Previous EGFR protein degraders showed efficacy against some triple mutants but not the Del19/T790M/C797S variant.

Purpose of the Study:

• To design and synthesize novel EGFR proteolysis-targeting chimeras (PROTACs) targeting the Del19/T790M/C797S triple mutant.
• To evaluate the efficacy of these PROTACs in degrading the target EGFR mutant and inhibiting cancer cell proliferation.

Main Methods:

• Design and synthesis of a series of EGFR-targeting PROTACs.
• Assessment of EGFR degradation in Ba/F3 cells expressing the EGFR Del19/T790M/C797S mutant.
• Evaluation of antiproliferation activity of lead compounds.

Main Results:

• Compound 6h demonstrated potent and rapid degradation of the EGFR Del19/T790M/C797S mutant in a time- and dose-dependent manner (DC50 = 8 nM).
• Compound 6h exhibited significant antiproliferation activity against Ba/F3-EGFR Del19/T790M/C797S cells (IC50 = 0.02 μM).

Conclusions:

• The developed EGFR PROTACs, particularly compound 6h, are effective in degrading the EGFR Del19/T790M/C797S triple mutant.
• Compound 6h represents a promising lead for developing new therapeutic agents for non-small cell lung cancer patients with EGFR C797S resistance mutations.