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

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 mu M) and selective inhibitor. Protein mass spectrometry confirmed the covalent reaction with the catalytically active cysteine-79.

Automated summary

The DNA methyltransferase 2 (DNMT2) is an RNA modifying enzyme that plays a role in various pathophysiological processes, including mental and metabolic disorders and cancer. In this study, covalent SAH-based DNMT2 inhibitors were developed and tested for their effectiveness. A 4-bromo-3-nitrophenylsulfonamide-decorated SAH derivative (80) was found to be the most potent and selective inhibitor, with confirmed covalent reaction with the catalytically active cysteine-79.