Inhibitors of UHRF1 base flipping activity showing cytotoxicity against cancer cells

Stefano Ciaco (1, 2) , Viola Mazzoleni (1) , Aqib Javed (1) , Sylvia Eiler (3) , Marc Ruff (3) , Marc Mousli (1) , Mattia Mori (2) , Yves Mély (1)

1 LBP - Laboratoire de Bioimagerie et Pathologies
2 UNISI - Università degli Studi di Siena = University of Siena
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

Ubiquitin-like containing PHD and RING finger domain 1 (UHRF1) is a nuclear multi-domain protein overexpressed in numerous human cancer types. We previously disclosed the anthraquinone derivative UM63 that inhibits UHRF1-SRA domain base-flipping activity, although having DNA intercalating properties. Herein, based on the UM63 structure, new UHRF1-SRA inhibitors were identified through a multidisciplinary approach, combining molecular modelling, biophysical assays, molecular and cell biology experiments. We identified AMSA2 and MPB7, that inhibit UHRF1-SRA mediated base flipping at low micromolar concentrations, but do not intercalate into DNA, which is a key advantage over UM63. These molecules prevent UHRF1/DNMT1 interaction at replication forks and decrease the overall DNA methylation in cells. Moreover, both compounds specifically induce cell death in numerous cancer cell lines, displaying marginal effect on non-cancer cells, as they preferentially affect cells with high level of UHRF1. Overall, these two compounds are promising leads for the development of anti-cancer drugs targeting UHRF1.

Mots clés: Epigenetics; DNA methylation; UHRF1 base flipping inhibitors; Fluorescence; Virtual screening

Domaines: Cancer; Pharmacologie

Stefano Ciaco, Viola Mazzoleni, Aqib Javed, Sylvia Eiler, Marc Ruff, et al.. Inhibitors of UHRF1 base flipping activity showing cytotoxicity against cancer cells. Bioorganic Chemistry, 2023, 137, pp.106616. ⟨10.1016/j.bioorg.2023.106616⟩. ⟨hal-04238876⟩