Design and synthesis of new non nucleoside inhibitors of DNMT3A

  • Bioorg Med Chem. 2015 Sep 1;23(17):5946-53. doi: 10.1016/j.bmc.2015.06.066.
Alexandre Erdmann  1 ,  Yoann Menon  1 ,  Christina Gros  1 ,  Nicolas Molinier  1 ,  Natacha Novosad  1 ,  Arnaud Samson  1 ,  Jean-Marc Gregoire  1 ,  Christophe Long  1 ,  Frédéric Ausseil  1 ,  Ludovic Halby  1 ,  Paola B Arimondo  2
Affiliations
  • 1. Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
  • 2. Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France. Electronic address: [email protected].
PMID: 26220519 DOI: 10.1016/j.bmc.2015.06.066
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.

Keywords
DNA methylation; DNMT3A; Michael acceptor; Reactive inhibitor.