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Open AccessArticle

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

1
X-Chem Pharmaceuticals, Waltham, MA 02435, USA
2
Arrakis Therapeutics, Waltham, MA 02451, USA
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Author to whom correspondence should be addressed.
Molecules 2019, 24(10), 2026; https://doi.org/10.3390/molecules24102026
Received: 25 April 2019 / Revised: 15 May 2019 / Accepted: 20 May 2019 / Published: 27 May 2019
(This article belongs to the Special Issue DNA-Encoded Chemical Libraries)
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. View Full-Text
Keywords: DNA-encoded chemical library; affinity-mediated selection; G-quartet; c-myc; SPR DNA-encoded chemical library; affinity-mediated selection; G-quartet; c-myc; SPR
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Litovchick, A.; Tian, X.; Monteiro, M.I.; Kennedy, K.M.; Guié, M.-A.; Centrella, P.; Zhang, Y.; Clark, M.A.; Keefe, A.D. Novel Nucleic Acid Binding Small Molecules Discovered Using DNA-Encoded Chemistry. Molecules 2019, 24, 2026.

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