LAUSR

Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of S-adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics. Inhibitors causing both full and partial inhibition of purified DNMT1 were characterized. The inhibitors show modest selectivity for DNMT1 versus DNMT3b. Active-site docking predicts inhibitor interactions with S-adenosyl-l-methionine and deoxycytidine regions of the catalytic site, validated by direct binding analysis. Inhibitor action with purified DNMT1 is not reflected in cultured cells. A partial inhibitor activated cellular DNA methylation, and a full inhibitor had no effect on cellular DNA methylation. These compounds provide chemical access to a new family of noncovalent DNMT chemical scaffolds for use in DNA methyltransferases.