# Targeted Degradation of eEF2K by a Structure‐Guided PROTAC Strategy for the Treatment of Triple‐Negative Breast Cancer

## TL;DR

Researchers developed a new drug, A6, that targets and degrades a specific protein (eEF2K) in triple-negative breast cancer cells, significantly reducing tumor growth and showing promise as a treatment.

## Contribution

A novel PROTAC molecule, A6, was developed to target eEF2K in triple-negative breast cancer with improved tumor-specific delivery via a pH-sensitive nanocarrier.

## Key findings

- A6, a PROTAC, achieved >90% degradation of eEF2K in TNBC cells while preserving its substrate eEF2.
- A6@ZIF-8, a pH-sensitive nanocarrier, enhanced drug accumulation at tumor sites and improved therapeutic outcomes in TNBC models.
- A6 inhibited tumor growth in vitro and in vivo with favorable tolerability in TNBC organoid models.

## Abstract

Proteolysis‐targeting chimera (PROTAC) have emerged as a promising class of anticancer agents. Eukaryotic elongation factor 2 kinase (eEF2K), a stress‐responsive regulator of translational elongation, has emerged as a pivotal therapeutic target in triple‐negative breast cancer (TNBC) due to its critical role in sustaining cancer cell survival under nutrient stress. Building on our previous work identifying eEF2K as an oncogenic kinase, this study developed an eEF2K‐targeting PROTAC that exhibited potent antitumor activity against TNBC. Through a structure‐guided design, we identified a key allosteric pocket of eEF2K and linked its inhibitor 2S to a CRBN ligand to generate A6, a PROTAC that promotes eEF2K degradation via a conformationally optimized interface, achieving >90% target depletion while preserving the total levels of its substrate eEF2. A6 exhibited anti‐proliferative effects across TNBC cell lines by degrading eEF2K. In Vivo and in TNBC organoid models, A6 treatment significantly suppressed tumor growth, with favorable tolerability. To further enhance tumor‐specific delivery, we engineered A6@ZIF‐8, a pH‐sensitive nanocarrier that promotes drug accumulation at tumor sites compared to free A6, leading to improved therapeutic outcomes. Collectively, our data indicate that targeted degradation of eEF2K via PROTAC technology constitutes a novel and therapeutically relevant intervention strategy for TNBC.

This study developed an eEF2K‐targeting PROTAC, A6, that efficiently degrades eEF2K in TNBC cells, inhibiting tumor growth in vitro and in vivo. To enhance tumor‐specific delivery, we engineered A6@ZIF‐8, a pH‐sensitive nanocarrier, which improved drug accumulation at tumor sites, offering a promising therapeutic strategy for TNBC through targeted degradation of eEF2K.