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

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

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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