DNA junction ligands trigger DNA damage and are synthetic lethal with DNA repair inhibitors in cancer cells

Katerina Duskova (1) , Pauline Lejault (1) , Élie Benchimol , Régis Guillot (2) , Sébastien Britton (3) , Anton Granzhan (4) , David Monchaud (1)

1 ICMUB - Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon]
2 ICMMO - Institut de Chimie Moléculaire et des Matériaux d'Orsay
3 IPBS - Institut de pharmacologie et de biologie structurale
4 Chimie, Modélisation et Imagerie pour la Biologie [Orsay]

Translocation of DNA and RNA polymerases along their duplex substrates results in DNA supercoiling. This torsional stress promotes the formation of plectonemic structures, including three-way DNA junction (TWJ), which can block DNA transactions and lead to DNA damage. While cells have evolved multiple mechanisms to prevent the accumulation of such structures, stabilizing TWJ through ad hoc ligands offer an opportunity to trigger DNA damage in cells with high level of transcription and replication, such as cancer cells. Here, we develop a series of azacryptand-based TWJ ligands, we thoroughly characterize their TWJ-interacting properties in vitro and demonstrate their capacity to trigger DNA damage in rapidly dividing human cancer cells. We also demonstrate that TWJ ligands are amenable to chemically induced synthetic lethality strategies upon association with inhibitors of DNA repair, thus paving the way towards innovative drug combinations to fight cancers.

Domaines: Chimie organique; Chimie thérapeutique; Sciences du Vivant [q-bio]; Cancer

Katerina Duskova, Pauline Lejault, Élie Benchimol, Régis Guillot, Sébastien Britton, et al.. DNA junction ligands trigger DNA damage and are synthetic lethal with DNA repair inhibitors in cancer cells. Journal of the American Chemical Society, 2019, ⟨10.1021/jacs.9b11150⟩. ⟨hal-02412757⟩