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Updated: Apr 6, 2026

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Design and synthesis of new non nucleoside inhibitors of DNMT3A
Alexandre Erdmann1, Yoann Menon1, Christina Gros1
1Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
Abstract:
DNA methylation, an epigenetic modification regulating gene expression, is a promising target in cancer. In an effort to identify new non nucleosidic inhibitors of DNA methyltransferases, the enzymes responsible for DNA methylation, we carried out a high-throughput screening of 66,000 chemical compounds based on an enzymatic assay against catalytic DNMT3A. A family of propiophenone derivatives was identified. After chemical optimization and structure activity relationship studies, a new inhibitor (33) was obtained with an EC50 of 2.1 μM against DNMT3A. The mechanism of inhibition of the compound was investigated as it forms a reactive Michael acceptor group in situ. Thereby, the Michael acceptor 20 was identified. This compound was further characterized for its biological activity in cancer cells.
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