Covalent <i>S</i>-Adenosylhomocysteine-Based DNA Methyltransferase 2 Inhibitors with a New Type of Aryl Warhead
Marvin Schwickert, Robert A. Zimmermann, Tanja Habeck, Sabrina N. Hoba, Zarina Nidoieva, Tim R. Fischer, Martin Stärk, Christian Kersten, Frederik Lermyte, Mark Helm, Tanja Schirmeister
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 (IC 50 = 1.2 ± 0.1 μM) and selective inhibitor. Protein mass spectrometry confirmed the covalent reaction with the catalytically active cysteine-79.