Repurposing AS1411 for constructing ANM-PROTACs.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Proteolysis-targeting chimeras (PROTACs) offer targeted protein degradation but face limitations like poor cell permeability and E3 ligase ligand potency.
• AS1411 is an antitumor aptamer that binds nucleolin (NCL), a protein involved in membrane-nucleus shuttling.

Purpose of the Study:

• To repurpose the AS1411 aptamer as an E3 ligase ligand for PROTAC development.
• To construct and evaluate an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) for targeted degradation of oncogenic proteins.

Main Methods:

• AS1411 was repurposed to anchor the NCL-MDM2 complex, serving as an E3 ligase ligand.
• ANM-PROTACs were synthesized by conjugating AS1411 with ligands for oncogenic proteins STAT3, c-Myc, p53-R175H, and AR-V7.
• The efficacy of ANM-PROTAC in tumor cell penetration, protein degradation, and in vivo antitumor activity was assessed.

Main Results:

• The ANM-PROTAC demonstrated efficient tumor cell penetration and recruitment of MDM2.
• Degradation of targeted oncogenic proteins (STAT3, c-Myc, p53-R175H, AR-V7) was achieved by the ANM-PROTAC.
• ANM-PROTAC exhibited tumor-selective distribution, potent antitumor activity, and no systemic toxicity.

Conclusions:

• The developed ANM-PROTAC leverages AS1411 for E3 ligase binding, overcoming PROTAC limitations.
• This novel PROTAC possesses inherent tumor-targeting and cell-penetrating capabilities.
• ANM-PROTAC represents a promising therapeutic strategy against cancers driven by "undruggable" oncogenes.