Enzyme-Induced Supramolecular Proteolysis-Targeting Chimeras Enable Tumor-Targeted Protein Degradation.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Conventional proteolysis-targeting chimeras (PROTACs) face challenges in tissue selectivity and the hook effect, limiting in vivo therapeutic efficacy.
• Targeted protein degradation (TPD) is a key strategy for modulating protein homeostasis and eliminating disease-associated proteins.

Purpose of the Study:

• To develop a novel TPD platform, enzyme-induced supramolecular PROTACs (eiSupTACs), for enhanced tumor-targeted protein degradation.
• To overcome limitations of conventional PROTACs regarding selectivity and the hook effect.

Main Methods:

• eiSupTACs were engineered from ligand conjugates with cysteine and 2-cyanobenzothiazole motifs for bioorthogonal assembly.
• Activation mechanism relies on tumor-specific enzymes like cathepsin B and elevated glutathione for nanoparticle formation.
• Demonstrated selective degradation of bromodomain protein 4 and glutathione peroxidase 4 (GPX4) in cancer cell lines.

Main Results:

• eiSupTACs selectively assembled into multivalent nanoparticles within tumor cells, enhancing protein degradation.
• Potent and selective degradation of target proteins (BRD4, GPX4) was observed in cancer cells, with minimal impact on nonmalignant cells.
• GPX4 degradation induced ferroptosis and suppressed tumor growth in a murine xenograft model.

Conclusions:

• Established a modular and tumor-selective TPD platform using eiSupTACs.
• eiSupTACs offer a generalizable strategy for spatiotemporally resolved protein homeostasis modulation in targeted cancer therapy.