Natural G-Quadruplex Stabilizers: A Targeted Strategy for Breast Cancer Therapy

Area of Science:

• Genomics and Molecular Biology
• Pharmacology and Drug Discovery
• Oncology

Background:

• G-quadruplexes (G4s) are non-canonical DNA structures vital for gene regulation, telomere maintenance, and implicated in cancer development.
• Breast cancer (BC) exhibits G4 enrichment in oncogene promoters (e.g., c-MYC, HER2), presenting therapeutic targets.
• While synthetic G4 stabilizers are studied, natural products offer a less explored avenue for selective, biocompatible, and multi-target ligands.

Purpose of the Study:

• To systematically review and analyze natural compounds with G4-stabilizing effects, focusing on their potential application in breast cancer (BC).
• To define the interactions between G4 ligands and map these compounds to BC-associated genomic regions.
• To identify research gaps and propose a roadmap for natural G4 stabilizer drug discovery for BC.

Main Methods:

• Systematic literature review and analysis of natural compounds (flavonoids, alkaloids, polyphenols, terpenoids, organosulfur compounds) exhibiting G4-stabilizing properties.
• Landscape approach to define G4-ligand interactions, including stabilization mechanisms (π-π stacking, electrostatic interactions, groove binding).
• Mapping of identified compounds to genomic regions associated with G4 formation in breast cancer.

Main Results:

• Identified various natural compound classes with G4-stabilizing effects, showing potential for BC therapy.
• Detailed interactions between G4 ligands and stabilization mechanisms were analyzed.
• Key research gaps identified: limited in vivo validation, lack of subtype-specific efficacy data, and pharmacokinetic challenges.

Conclusions:

• Natural G4 stabilizers demonstrate promise as multi-target, biocompatible agents for breast cancer (BC) therapy.
• Current effectiveness is limited by insufficient in vivo studies and subtype-specific data.
• A prospective roadmap involving in silico docking, mechanistic studies, and translational strategies is proposed for future drug discovery.