Discovery of Inhibitors of DNA Methyltransferase 2, an Epitranscriptomic Modulator and Potential Target for Cancer Treatment

Selective manipulation of the epitranscriptome could
be beneficial
for the treatment of cancer and also broaden the understanding of
epigenetic inheritance. Inhibitors of the tRNA methyltransferase DNMT2,
the enzyme catalyzing the S-adenosylmethionine-dependent
methylation of cytidine 38 to 5-methylcytidine, were designed, synthesized,
and analyzed for their enzyme-binding and -inhibiting properties.
For rapid screening of potential DNMT2 binders, a microscale thermophoresis
assay was established. Besides the natural inhibitors S-adenosyl-l-homocysteine (SAH) and sinefungin (SFG), we
identified new synthetic inhibitors based on the structure of N-adenosyl-2,4-diaminobutyric acid (Dab). Structure–activity
relationship studies revealed the amino acid side chain and a Y-shaped
substitution pattern at the 4-position of Dab as crucial for DNMT2
inhibition. The most potent inhibitors are alkyne-substituted derivatives,
exhibiting similar binding and inhibitory potencies as the natural
compounds SAH and SFG. CaCo-2 assays revealed that poor membrane permeabilities
of the acids and rapid hydrolysis of an ethylester prodrug might be
the reasons for the insufficient activity in cellulo.