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

• Main Authors: Alexander Litovchick, Xia Tian, Michael I. Monteiro, Kaitlyn M. Kennedy, Marie-Aude Guié, Paolo Centrella, Ying Zhang, Matthew A. Clark, Anthony D. Keefe
• Format: Article
• Language: English
• Published: MDPI AG 2019-05-01
• Series: Molecules
• Subjects: DNA-encoded chemical library; affinity-mediated selection; G-quartet; c-myc; SPR
• Online Access: https://www.mdpi.com/1420-3049/24/10/2026

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 <i>c-myc</i> 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.