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

Duskova K; Lamarche J; Amor S; Caron C; Queyriaux N; Gaschard M; Penouilh MJ; de Robillard G; Delmas D; Devillers CH; Granzhan A; Teulade-Fichou MP; Chavarot-Kerlidou M; Therrien B; Britton S; Monchaud D

doi:10.1021/acs.jmedchem.8b01978

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Journal article

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

Duskova K Institut de Chimie Moléculaire (ICMUB), CNRS UMR6302, UBFC , 21078 Dijon , France.
Lamarche J Institut de Chimie Moléculaire (ICMUB), CNRS UMR6302, UBFC , 21078 Dijon , France.
Amor S Lipids, Nutrition & Cancers (LNC), INSERM U1321, UBFC , 21000 Dijon , France.
Caron C Institut Curie, PSL Research University, CNRS UMR9187, INSERM U1196 , 91405 Orsay , France.
Queyriaux N Laboratoire de Chimie et Biologie des Métaux , Université Grenoble Alpes, CNRS UMR5249, CEA , 38054 Grenoble , France.
Gaschard M Institut de Chimie , Université de Neuchâtel , CH-2000 Neuchatel , Switzerland.
Penouilh MJ Pôle Chimie Moléculaire (PACSMUB) , Faculté des Sciences Mirande, UBFC , 21078 Dijon , France.
de Robillard G Institut de Chimie Moléculaire (ICMUB), CNRS UMR6302, UBFC , 21078 Dijon , France.
Delmas D Lipids, Nutrition & Cancers (LNC), INSERM U1321, UBFC , 21000 Dijon , France.
Devillers CH Institut de Chimie Moléculaire (ICMUB), CNRS UMR6302, UBFC , 21078 Dijon , France.
Granzhan A Institut Curie, PSL Research University, CNRS UMR9187, INSERM U1196 , 91405 Orsay , France.
Teulade-Fichou MP Institut Curie, PSL Research University, CNRS UMR9187, INSERM U1196 , 91405 Orsay , France.
Chavarot-Kerlidou M Laboratoire de Chimie et Biologie des Métaux , Université Grenoble Alpes, CNRS UMR5249, CEA , 38054 Grenoble , France.
Therrien B Institut de Chimie , Université de Neuchâtel , CH-2000 Neuchatel , Switzerland.
Britton S Institut de Pharmacologie et de Biologie Structurale, IPBS, CNRS UMR5089, Université de Toulouse, UPS, équipe labellisée la Ligue Contre le Cancer , 31077 Toulouse , France.
Monchaud D Institut de Chimie Moléculaire (ICMUB), CNRS UMR6302, UBFC , 21078 Dijon , France.

2019-04-04

Published in:

Journal of medicinal chemistry. - 2019

Electrophoresis, Polyacrylamide Gel

Fluorescence Resonance Energy Transfer

Spectrometry, Mass, Electrospray Ionization

English 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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