PROTAC approaches against drug-resistant EGFR^{C797S/L858R/T790M} mutants: biological evaluation and SAR studies...

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Epidermal growth factor receptor (EGFR) mutations, specifically C797S/L858R/T790M, confer resistance to tyrosine kinase inhibitors (TKIs).
• This resistance mechanism involves reduced drug binding and increased adenosine triphosphate (ATP) competition, sustaining EGFR signaling.
• The rising rates of TKI resistance necessitate novel therapeutic approaches targeting both wild-type and mutated EGFR.

Purpose of the Study:

• To review and compile recent advancements in EGFR-directed Proteolysis-Targeting Chimeras (PROTACs) designed to combat C797S/L858R/T790M-mediated resistance.
• To discuss the medicinal chemistry, structure-activity relationships (SAR), and optimization strategies for these next-generation EGFR degraders.

Main Methods:

• Literature review of studies published between 2020-2025 focusing on EGFR-targeted PROTACs.
• Analysis of reported PROTACs for their efficacy against specific EGFR mutations (C797S, L858R, T790M).
• Examination of medicinal chemistry aspects, SAR, and degradation efficiency of identified PROTACs.

Main Results:

• Several EGFR-directed PROTACs have demonstrated significant activity against EGFR mutations conferring TKI resistance.
• These PROTACs function via protein degradation, offering an alternative to traditional enzymatic inhibition.
• Key features influencing binding and degradation efficiency have been identified for improved PROTAC design.

Conclusions:

• PROTAC-based degraders represent a promising next-generation therapeutic strategy for overcoming EGFR TKI resistance.
• These molecules can effectively eliminate wild-type and mutated EGFR, bypassing limitations of classical inhibitors.
• Further development of PROTACs holds potential for improved treatment outcomes in EGFR-mutated cancers.