Junctions in DNA: underexplored targets for therapeutic intervention

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• Deoxyribonucleic acid (DNA) is a primary target in cancer therapy, with existing compounds inducing damage or impairing its processing.
• Achieving sequence-specific targeting of DNA with small molecules to modulate gene-specific processes remains a significant challenge in oncology.

Purpose of the Study:

• To review small molecules designed to bind to non-canonical DNA structures.
• To explore the potential of targeting DNA three- and four-way junctions for novel cancer treatments.

Main Methods:

• Literature review of reported small molecules interacting with DNA.
• Focus on compounds binding to specific non-double helical DNA conformations, namely three- and four-way junctions.

Main Results:

• Identification of various small molecules capable of binding to DNA three- and four-way junctions.
• These non-canonical structures present unique binding pockets distinct from the classical double helix.

Conclusions:

• Exploiting alternative DNA structures like junctions offers a promising strategy for developing sequence-specific therapeutic agents.
• Small molecules targeting these junctions represent a potential new avenue for cancer therapy beyond conventional DNA-damaging agents.