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

Molecules. 2019 May 27;24(10):2026. doi: 10.3390/molecules24102026.


Inspired by the many reported successful applications of DNA-encoded chemical libraries in drug discovery projects with protein targets, we decided to apply this platform to nucleic acid targets. We used a 120-billion-compound set of 33 distinct DNA-encoded chemical libraries and affinity-mediated selection to discover binders to a panel of DNA targets. Here, we report the successful discovery of small molecules that specifically interacted with DNA G-quartets, which are stable structural motifs found in G-rich regions of genomic DNA, including in the promoter regions of oncogenes. For this study, we chose the G-quartet sequence found in the c-myc promoter as a primary target. Compounds enriched using affinity-mediated selection against this target demonstrated high-affinity binding and high specificity over DNA sequences not containing G-quartet motifs. These compounds demonstrated a moderate ability to discriminate between different G-quartet motifs and also demonstrated activity in a cell-based assay, suggesting direct target engagement in the cell. DNA-encoded chemical libraries and affinity-mediated selection are uniquely suited to discover binders to targets that have no inherent activity outside of a cellular context, and they may also be of utility in other nucleic acid structural motifs.

Keywords: DNA-encoded chemical library; G-quartet; SPR; affinity-mediated selection; c-myc.

MeSH terms

  • Cell Line, Tumor
  • Cell Survival
  • DNA / chemistry*
  • Drug Discovery*
  • Humans
  • Small Molecule Libraries*
  • Surface Plasmon Resonance


  • Small Molecule Libraries
  • DNA