Identification of Three-Way DNA Junction Ligands through Screening of Chemical Libraries and Validation by Complementary in Vitro Assays

Abstract : 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, 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, PAGE, FRET-melting, ESI-MS, dialysis equilibrium and SRB 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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Katerina Duskova, Jérémy Lamarche, Souheila Amor, Coralie Caron, Nicolas Queyriaux, et al.. Identification of Three-Way DNA Junction Ligands through Screening of Chemical Libraries and Validation by Complementary in Vitro Assays. Journal of Medicinal Chemistry, American Chemical Society, 2019, 62 (9), pp.4456-4466. ⟨10.1021/acs.jmedchem.8b01978⟩. ⟨hal-02121543v3⟩

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