Novel Nucleic Acid Binding Small Molecules Discovered Using DNA-Encoded Chemistry

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Genomics

Background:

• DNA-encoded chemical libraries (DELs) have shown success in drug discovery against protein targets.
• Nucleic acid structures, such as G-quartets, are increasingly recognized as potential therapeutic targets.
• The c-myc promoter G-quartet is implicated in oncogenesis.

Purpose of the Study:

• To apply the DNA-encoded chemical library platform for the discovery of small molecule binders to DNA targets.
• To identify compounds that specifically interact with DNA G-quartet motifs.
• To evaluate the cellular activity and specificity of identified binders.

Main Methods:

• Utilized a large-scale DNA-encoded chemical library (120 billion compounds, 33 libraries).
• Employed affinity-mediated selection against a specific G-quartet DNA sequence from the c-myc promoter.
• Validated binders using biophysical assays for affinity and specificity, and cell-based assays for activity.

Main Results:

• Successfully discovered small molecules with high-affinity and high specificity for DNA G-quartets.
• Identified compounds that showed moderate discrimination between different G-quartet motifs.
• Demonstrated cell-based activity, indicating target engagement within a cellular environment.

Conclusions:

• DNA-encoded libraries and affinity-mediated selection are effective for discovering binders to nucleic acid targets, including G-quartets.
• The identified compounds show potential for therapeutic development against targets like the c-myc oncogene.
• This platform is suitable for discovering binders to targets lacking inherent extracellular activity and may be applicable to other nucleic acid structures.