Targeted Degradation of eEF2K by a Structure-Guided PROTAC Strategy for the Treatment of Triple-Negative Breast...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Eukaryotic elongation factor 2 kinase (eEF2K) is a key therapeutic target in triple-negative breast cancer (TNBC).
• eEF2K regulates cancer cell survival under nutrient stress.
• Targeting eEF2K offers a promising strategy for TNBC treatment.

Purpose of the Study:

• To develop and evaluate a novel proteolysis-targeting chimera (PROTAC) targeting eEF2K for TNBC therapy.
• To investigate the mechanism of action and antitumor efficacy of the eEF2K-targeting PROTAC.

Main Methods:

• Structure-guided design of an eEF2K-targeting PROTAC (A6) by linking an eEF2K inhibitor (2S) to a CRBN ligand.
• Assessment of A6-mediated eEF2K degradation in TNBC cell lines.
• Evaluation of A6's anti-proliferative effects in vitro and in vivo TNBC models.
• Engineering of a pH-sensitive nanocarrier (A6@ZIF-8) for enhanced tumor-specific delivery.

Main Results:

• The developed PROTAC, A6, achieved >90% degradation of eEF2K while preserving its substrate eEF2 levels.
• A6 demonstrated potent anti-proliferative effects across various TNBC cell lines.
• In vivo and organoid models showed significant suppression of tumor growth with favorable tolerability.
• The A6@ZIF-8 nanocarrier enhanced drug accumulation at tumor sites, improving therapeutic outcomes.

Conclusions:

• Targeted degradation of eEF2K using PROTAC technology is a novel and effective therapeutic strategy for TNBC.
• A6 represents a promising eEF2K-targeting PROTAC with significant antitumor activity.
• Engineered nanocarriers can improve the tumor-specific delivery and efficacy of PROTACs for TNBC treatment.