Synthesis and degradation effect of PROTACs targeting EGFR triple mutants

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Epidermal growth factor receptor (EGFR) mutations drive cancer drug resistance, limiting the effectiveness of EGFR tyrosine kinase inhibitors (EGFR-TKIs).
• Addressing resistance, particularly triple mutations like EGFR^{Del19/T790M/C797S} and EGFR^{L858R/T790M/C797S}, is crucial for improving patient outcomes.

Purpose of the Study:

• To design and synthesize novel Proteolysis-Targeting Chimeras (PROTACs) capable of degrading EGFR triple mutants.
• To evaluate the antiproliferative activity and degradation efficacy of newly designed PROTAC compounds against EGFR-mutant cancer cells.

Main Methods:

• Utilized fourth-generation EGFR-TKIs and VHL-ligands with acyl linkers to construct PROTACs targeting EGFR triple mutants.
• Synthesized and screened a library of 12 PROTAC compounds (EP1-EP12).
• Investigated the mechanism of EGFR degradation, including ternary complex formation, ubiquitination, and lysosomal pathway involvement.

Main Results:

• Compounds EP7, EP8, EP9, EP11, and EP12 demonstrated potent antiproliferative effects on EGFR-mutant cells.
• EP9 and EP12 significantly induced the degradation of EGFR triple mutants (EGFR^{Del19/T790M/C797S} and EGFR^{L858R/T790M/C797S}).
• These PROTACs effectively suppressed EGFR pathway signaling and required ubiquitination and lysosomal activity for degradation.

Conclusions:

• Compounds EP9 and EP12 are identified as effective PROTAC degraders of EGFR triple mutants.
• These findings provide valuable insights for developing novel PROTAC-based therapies to overcome EGFR-TKI resistance.
• The study highlights the potential of PROTAC technology in targeting challenging cancer mutations.