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

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 May 30

PMID 31137911

Citations 10

Authors

Alexander Litovchick

Xia Tian

Michael I Monteiro

Kaitlyn M Kennedy

Marie-Aude Guie

Paolo Centrella

Ying Zhang

Matthew A Clark

Anthony D Keefe

Affiliations

Soon will be listed here.

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 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.

Citing Articles

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References

Bemark M, Neuberger M . The c-MYC allele that is translocated into the IgH locus undergoes constitutive hypermutation in a Burkitt's lymphoma line. Oncogene. 2000; 19(30):3404-10. DOI: 10.1038/sj.onc.1203686. View

Siddiqui-Jain A, Grand C, Bearss D, Hurley L . Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci U S A. 2002; 99(18):11593-8. PMC: 129314. DOI: 10.1073/pnas.182256799. View

Lemarteleur T, Gomez D, Paterski R, Mandine E, Mailliet P, Riou J . Stabilization of the c-myc gene promoter quadruplex by specific ligands' inhibitors of telomerase. Biochem Biophys Res Commun. 2004; 323(3):802-8. DOI: 10.1016/j.bbrc.2004.08.150. View

Ou T, Lu Y, Zhang C, Huang Z, Wang X, Tan J . Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc by quindoline derivatives. J Med Chem. 2007; 50(7):1465-74. DOI: 10.1021/jm0610088. View

Sedoris K, Thomas S, Miller D . c-myc promoter binding protein regulates the cellular response to an altered glucose concentration. Biochemistry. 2007; 46(29):8659-68. DOI: 10.1021/bi7003558. View

Gonzalez V, Guo K, Hurley L, Sun D . Identification and characterization of nucleolin as a c-myc G-quadruplex-binding protein. J Biol Chem. 2009; 284(35):23622-35. PMC: 2749137. DOI: 10.1074/jbc.M109.018028. View

Neidle S . Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer. FEBS J. 2009; 277(5):1118-25. DOI: 10.1111/j.1742-4658.2009.07463.x. View

Zahler A, Williamson J, Cech T, Prescott D . Inhibition of telomerase by G-quartet DNA structures. Nature. 1991; 350(6320):718-20. DOI: 10.1038/350718a0. View

Yang D, Okamoto K . Structural insights into G-quadruplexes: towards new anticancer drugs. Future Med Chem. 2010; 2(4):619-46. PMC: 2886307. DOI: 10.4155/fmc.09.172. View

10.

Balasubramanian S, Hurley L, Neidle S . Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?. Nat Rev Drug Discov. 2011; 10(4):261-75. PMC: 3119469. DOI: 10.1038/nrd3428. View

11.

Mathad R, Hatzakis E, Dai J, Yang D . c-MYC promoter G-quadruplex formed at the 5'-end of NHE III1 element: insights into biological relevance and parallel-stranded G-quadruplex stability. Nucleic Acids Res. 2011; 39(20):9023-33. PMC: 3203601. DOI: 10.1093/nar/gkr612. View

12.

Brown R, Danford F, Gokhale V, Hurley L, Brooks T . Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex. J Biol Chem. 2011; 286(47):41018-27. PMC: 3220475. DOI: 10.1074/jbc.M111.274720. View

13.

Yuan L, Tian T, Chen Y, Yan S, Xing X, Zhang Z . Existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy. Sci Rep. 2013; 3:1811. PMC: 3648798. DOI: 10.1038/srep01811. View

14.

Shalaby T, Fiaschetti G, Nagasawa K, Shin-Ya K, Baumgartner M, Grotzer M . G-quadruplexes as potential therapeutic targets for embryonal tumors. Molecules. 2013; 18(10):12500-37. PMC: 6269990. DOI: 10.3390/molecules181012500. View

15.

Litovchick A, Clark M, Keefe A . Universal strategies for the DNA-encoding of libraries of small molecules using the chemical ligation of oligonucleotide tags. Artif DNA PNA XNA. 2014; 5(1):e27896. PMC: 4014522. DOI: 10.4161/adna.27896. View

16.

Keefe A, Clark M, Hupp C, Litovchick A, Zhang Y . Chemical ligation methods for the tagging of DNA-encoded chemical libraries. Curr Opin Chem Biol. 2015; 26:80-8. DOI: 10.1016/j.cbpa.2015.02.015. View

17.

Litovchick A, Dumelin C, Habeshian S, Gikunju D, Guie M, Centrella P . Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library. Sci Rep. 2015; 5:10916. PMC: 4603778. DOI: 10.1038/srep10916. View

18.

Felsenstein K, Saunders L, Simmons J, Leon E, Calabrese D, Zhang S . Small Molecule Microarrays Enable the Identification of a Selective, Quadruplex-Binding Inhibitor of MYC Expression. ACS Chem Biol. 2015; 11(1):139-48. PMC: 4719142. DOI: 10.1021/acschembio.5b00577. View

19.

Zimmermann G, Neri D . DNA-encoded chemical libraries: foundations and applications in lead discovery. Drug Discov Today. 2016; 21(11):1828-1834. PMC: 5214759. DOI: 10.1016/j.drudis.2016.07.013. View

20.

Soutter H, Centrella P, Clark M, Cuozzo J, Dumelin C, Guie M . Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology. Proc Natl Acad Sci U S A. 2016; 113(49):E7880-E7889. PMC: 5150407. DOI: 10.1073/pnas.1610978113. View