Covalent S-Adenosylhomocysteine-Based DNA Methyltransferase 2 Inhibitors with a New Type of Aryl Warhead

  • ACS Med Chem Lett. 2023 May 9;14(6):777-787. doi: 10.1021/acsmedchemlett.3c00062.
Marvin Schwickert  1 ,  Robert A Zimmermann  1 ,  Tanja Habeck  2 ,  Sabrina N Hoba  1 ,  Zarina Nidoieva  1 ,  Tim R Fischer  1 ,  Martin M Stark  1 ,  Christian Kersten  1 ,  Frederik Lermyte  2 ,  Mark Helm  1 ,  Tanja Schirmeister  1
Affiliations
  • 1. Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
  • 2. Technical University of Darmstadt, Alarich-Weiss-Strasse 4, D-64287 Darmstadt, Germany.
PMID: 37312859 DOI: 10.1021/acsmedchemlett.3c00062
Abstract

The DNA Methyltransferase 2 (DNMT2) is an RNA modifying enzyme associated with pathophysiological processes, such as mental and metabolic disorders or Cancer. Although the development of methyltransferase inhibitors remains challenging, DNMT2 is not only a promising target for drug discovery, but also for the development of activity-based probes. Here, we present covalent SAH-based DNMT2 inhibitors decorated with a new type of aryl warhead. Based on a noncovalent DNMT2 inhibitor with N-benzyl substituent, the Topliss scheme was followed for optimization. The results showed that electron-deficient benzyl moieties highly increased affinity. By decorating the structures with strong electron-withdrawing moieties and leaving groups, we adjusted the electrophilicity to create covalent DNMT2 inhibitors. A 4-bromo-3-nitrophenylsulfonamide-decorated SAH derivative (80) turned out to be the most potent (IC50 = 1.2 ± 0.1 μM) and selective inhibitor. Protein mass spectrometry confirmed the covalent reaction with the catalytically active cysteine-79.

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