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Tandem virtual screening targeting the SRA domain of UHRF1 identifies a novel chemical tool modulating DNA methylation

Abstract : Ubiquitin-like protein UHRF1 that contains PHD and RING finger domain 1 is a key epigenetic protein enabling maintenance of the DNA methylation status through replication. A tandem virtual screening approach was implemented for identifying small molecules able to bind the 5-methylcytosine pocket of UHRF1 and inhibit its functionality. The NCI/DTP small molecules Repository was screened in silico by a combined protocol implementing structure-based and ligand-based methodologies. Consensus ranking was utilized to select a set of 27 top-ranked compounds that were subsequently evaluated experimentally in a stepwise manner for their ability to demethylate DNA in cellulo using PCR-MS and HPLC-MS/MS. The most active molecules were further assessed in a cell-based setting by the Proximity Ligation In Situ Assay and the ApoTome technology. Both evaluations confirmed that the DNMT1/UHRF1 interactions were significantly reduced after 4 h of incubation of U251 glioma cells with the most potent compound NSC232003, showing a 50% interaction inhibition at 15 mM as well as induction of global DNA cytosine demethylation as measured by ELISA. This is the first report of a chemical tool that targets UHRF1 and modulates DNA methylation in a cell context by potentially disrupting DNMT1/UHRF1 interactions. Compound NSC232003, a uracil derivative freely available by the NCI/DTP Repository, provides a versatile lead for developing highly potent and cell-permeable UHRF1 inhibitors that will enable dissection of DNA methylation inheritance.
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Submitted on : Monday, December 12, 2016 - 10:59:14 AM
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Vassilios Myrianthopoulos, Pierre-Francois Cartron, Zita Liutkeviciute, Saulius Klimasauskas, Daumantas Matulis, et al.. Tandem virtual screening targeting the SRA domain of UHRF1 identifies a novel chemical tool modulating DNA methylation. European Journal of Medicinal Chemistry, Elsevier, 2016, 114, pp.390 - 396. ⟨10.1016/j.ejmech.2016.02.043⟩. ⟨inserm-01414204⟩



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