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

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 s...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2019-05, Vol.24 (10), p.2026
Main Authors: Litovchick, Alexander, Tian, Xia, Monteiro, Michael I, Kennedy, Kaitlyn M, Guié, Marie-Aude, Centrella, Paolo, Zhang, Ying, Clark, Matthew A, Keefe, Anthony D
Format: Article
Language:English
Subjects:
Affinity
affinity-mediated selection
Binders
Binding
c-myc
c-Myc protein
Cell Line, Tumor
Cell Survival
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA-encoded chemical library
Drug Discovery
G-quartet
Humans
Kinases
Lymphoma
Myc protein
Nucleic acids
Nucleotide sequence
Proteins
Small Molecule Libraries
SPR
Surface Plasmon Resonance
Telomerase
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Summary: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 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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules24102026