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Molecules. 2019 May 27;24(10). pii: E2026. doi: 10.3390/molecules24102026.

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

Author information

1
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. alitovchick@x-chemrx.com.
2
Arrakis Therapeutics, Waltham, MA 02451, USA. xia2tian@hotmail.com.
3
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. mmonteiro@x-chemrx.com.
4
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. Kaitlyn.kennedy1288@gmail.com.
5
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. mguie@x-chemrx.com.
6
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. pcentrella@x-chemrx.com.
7
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. yzhang@x-chemrx.com.
8
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. mclark@x-chemrx.com.
9
X-Chem Pharmaceuticals, Waltham, MA 02435, USA. akeefe@x-chemrx.com.

Abstract

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

Conflict of interest statement

The authors declare no conflicts of interest and are all current or former employees of X-Chem Pharmaceuticals.

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