Targeting G-Quadruplex DNA for Cancer Chemotherapy

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• DNA self-associates into guanine quadruplexes (G4s) via Hoogsteen hydrogen bonding, forming layered structures with distinct tetrads and loops.
• G4 structures offer unique recognition sites for small molecules and ligands, presenting potential as anticancer therapeutics.
• G4-selective ligands can modulate gene expression by targeting nucleic acid structure, impacting pathways like telomere maintenance and transcription.

Purpose of the Study:

• To review recent advancements in synthetic G4 DNA-interacting ligands.
• To explore the potential of these ligands as a strategy for discovering targeted anticancer chemotherapeutic agents.
• To highlight how G4 ligands can be designed to target specific G4 structures and loops for improved selectivity.

Main Methods:

• Review of current research on synthetic G4 DNA-interacting ligands.
• Analysis of how ligand modularity (functional groups, side chains, conformation) influences binding affinity and selectivity.
• Discussion of targeting specific G4 structures, including telomeric G4 and c-MYC, and oncogenic drivers like k-RAS.

Main Results:

• G4 ligands demonstrate potential for cancer treatment by targeting telomerase activity and influencing transcription.
• Small molecules can directly target k-RAS oncogenes, crucial in various cancers and drug resistance.
• Modular G4 ligands can be designed to exploit the diversity of G4 loops and grooves, leading to more selective and drug-like compounds.

Conclusions:

• Synthetic G4 ligands represent a promising avenue for developing targeted anticancer therapies.
• Ligand design can be tailored to achieve selectivity for specific G4 structures, enhancing therapeutic efficacy.
• Further research into G4-interacting ligands could yield novel chemotherapeutic agents against challenging cancers.