Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 9, Pages 4456-4466Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01978
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Funding
- European Union's Horizon 2020 research and innovation program [H2020-MSCA-IF-2016-750368]
- Agence Nationale de la Recherche [ANR-17-CE17-0010-01]
- IDEX Paris Saclay (IDI 2016) [ANR-11-IDEX-0003-02]
- Universite de Bourgogne and Conseil Regional de Bourgogne (PARI)
- European Union (PO FEDER-FSE Bourgogne 2014/2020 programs)
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The human genome is replete with repetitive DNA sequences that can fold into thermodynamically stable secondary structures such as hairpins and quadruplexes. Cellular enzymes exist to cope with these structures whose stable accumulation would result in DNA damage through interference with DNA transactions such as transcription and replication. Therefore, the chemical stabilization of secondary DNA structures offers an attractive way to foster DNA transaction-associated damages to trigger cell death in proliferating cancer cells. While much emphasis has been recently given to DNA quadruplexes, we focused here on three-way DNA junctions (TWJ) and report on a strategy to identify TWJ-targeting agents through a combination of in vitro techniques (TWJ-screen, polyacrylamide gel electrophoresis, fluorescence resonance energy transfer-melting, electrospray ionization mass spectrometry, dialysis equilibrium, and sulforhodamine B assays). We designed a complete workflow and screened 1200 compounds to identify promising TWJ ligands selected on stringent criteria in terms of TWJ-folding ability, affinity, and selectivity.
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