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

Autor:	Litovchick A; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. alitovchick@x-chemrx.com., Tian X; Arrakis Therapeutics, Waltham, MA 02451, USA. xia2tian@hotmail.com., Monteiro MI; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. mmonteiro@x-chemrx.com., Kennedy KM; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. Kaitlyn.kennedy1288@gmail.com., Guié MA; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. mguie@x-chemrx.com., Centrella P; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. pcentrella@x-chemrx.com., Zhang Y; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. yzhang@x-chemrx.com., Clark MA; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. mclark@x-chemrx.com., Keefe AD; X-Chem Pharmaceuticals, Waltham, MA 02435, USA. akeefe@x-chemrx.com.
Jazyk:	angličtina
Zdroj:	Molecules (Basel, Switzerland) [Molecules] 2019 May 27; Vol. 24 (10). Date of Electronic Publication: 2019 May 27.
DOI:	10.3390/molecules24102026
Abstrakt:	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. Competing Interests: The authors declare no conflicts of interest and are all current or former employees of X-Chem Pharmaceuticals.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu