Rational Design and Synthesis of Highly Stable Haloflavanone DNA Methyltransferase Inhibitors Inducing Tumor Suppressor Gene Re-expression in Cancer Cells

  • J Med Chem. 2025 Jun 12;68(11):10704-10721. doi: 10.1021/acs.jmedchem.4c02075.
Francesco Calzaferri  1 ,  Hiba Daher  2 ,  Julie Gilbert  1 ,  Yinshan Yang  3 ,  Marine Tauziet  2 ,  Corinne Jallet  4 ,  Yannick Bessin  1 ,  Arie van der Lee  5 ,  Paola Barbara Arimondo  4 ,  Isabelle Krimm  3  6 ,  Eric Julien  2  7 ,  Marie Lopez  1
Affiliations
  • 1. Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS-UM-ENSCM, 1919 route de Mende, Montpellier 34090, Cedex 5, France.
  • 2. Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM-UM-ICM, 08 avenue des Apothicaires, Montpellier 34298, Cedex 5, France.
  • 3. Centre de Biologie Structurale (CBS), CNRS-INSERM-UM, Montpellier 34090, France.
  • 4. Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, Université Paris Cité, UMR3523 CNRS Chem4Life, Paris F-75015, France.
  • 5. Institut Européen des Membranes (IEM), UMR 5635 CNRS-UM-ENSCM, 300 avenue du Prof. E. Jeanbrau, Montpellier 34296, Cedex 5, France.
  • 6. Univ. Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France.
  • 7. Centre National de la Recherche Scientifique (CNRS), Montpellier F-34293, France.
PMID: 40418195 DOI: 10.1021/acs.jmedchem.4c02075
Abstract

DNA methylation is an epigenetic modification involved in Cancer. The clinically approved nucleoside DNA Methyltransferase (DNMT) inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine lack selectivity and stability, resulting in high toxicity. Previously, we discovered 3-halo-3-nitroflavanones as non-nucleoside DNMT inhibitors. Here, we designed and synthesized a new series of 2-substituted haloflavanones to increase compound chemical stability. Moreover, replacement of the nitro by an additional halogen enhanced compound potency. Indeed, compound 34b (anti-3-bromo-3-chloro-2-methoxyflavanone) exhibited submicromolar DNMT3A inhibitory activity, upregulated the expression of DNMT-targeted genes, and impaired cell proliferation. Importantly, 34b triggered a critical cell cycle arrest in the G1/S transition, notably in p53-depleted HCT-116 colorectal Cancer cells, which paves the way for novel therapeutic opportunities. 34b competes for the same DNMT catalytic pocket as confirmed by saturation transfer difference-nuclear magnetic resonance, but assuming different docking poses as shown by computational studies. Overall, the high stability and activity of 34b make it a promising DNMT inhibitor for Anticancer research and therapy.

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