Discovery of Potent and Selective Epidermal Growth Factor Receptor (EGFR) Bifunctional Small-Molecule Degraders

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are standard treatments for non-small-cell lung cancer (NSCLC).
• Acquired resistance to EGFR inhibitors, driven by EGFR-mutant variants, remains a significant clinical challenge.
• Targeting protein degradation offers a novel therapeutic strategy to overcome drug resistance.

Purpose of the Study:

• To discover and characterize novel EGFR degraders using proteolysis targeting chimera (PROTAC) technology.
• To evaluate the efficacy and selectivity of these degraders against mutant EGFR in cancer cell lines.
• To assess the pharmacokinetic properties and in vivo potential of the developed compounds.

Main Methods:

• Utilized PROTAC technology to design and synthesize novel E3 ligase-recruiting EGFR degraders.
• Assessed compound-induced EGFR degradation in cancer cell lines using Western blotting and proteomic analyses.
• Evaluated anti-cancer efficacy through cell growth inhibition assays.
• Conducted pharmacokinetic studies in mice to determine compound bioavailability.

Main Results:

• Discovered MS39 (von Hippel-Lindau-recruiting) and MS154 (cereblon-recruiting) EGFR degraders.
• Demonstrated potent and selective degradation of mutant EGFR, but not wild-type EGFR, in an E3 ligase-dependent manner.
• Showed significant suppression of lung cancer cell growth by the novel degraders.
• Confirmed bioavailability of both compounds in mouse pharmacokinetic studies, with MS39 being suitable for in vivo efficacy studies.

Conclusions:

• MS39 and MS154 represent first-in-class EGFR degraders with potential therapeutic applications in NSCLC.
• PROTAC technology is effective for developing targeted protein degraders against EGFR.
• These well-characterized chemical tools will advance research in EGFR-targeted therapy and drug resistance.