Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors

Dimeric bisbenzimidazoles inhibit the DNA methylation catalyzed by the murine Dnmt3a catalytic domain

“…To summarize, we first found that compounds DB (1)(2)(3)(4)(5)7,11) are in vitro inhibitors of Dnmt3a-CD at low micromolar concentrations which is consistent with concentrations reported by others for different inhibitors of C5-MTases 15,34 . It is notable that the same range of concentrations (5-50 µM) of non-nucleoside MTase inhibitor was used in the case of cell culture assays 15 .…”

Epigenetic Therapies for Cancer

“…This drug works by blocking the catalytic pocket of DNMTS without the formation of covalent adducts that cause cytoxicity (Stressmann et al, 2006). Studies have also shown RG108 to cause demethylation and reactivation of tumor suppressor genes without affecting the methylation level of microsatellite regions in lung cancer cells (Suzuki et al, 2010), suggesting a specificity level in RG108 that has not been seen in other DNMTis. …”

Beyond Pharmacogenetics

“…Second-generation drugs that target epigenetic enzymes with more tightly defined modes of action are, at time of writing, still in the investigation phase. Some such drugs include MG98, an antisense oligonucleotide that targets the 3′-untranslated region of the maintenance methyltransferase DNMT1, inhibiting it (Goffin & Eisenhauer, 2002); RG108, a small molecule that effectively blocks DNMTs, particularly DNMT1 and inhibits their activity (Suzuki et al, 2010), and psammaplin, a natural product derived from the sea sponge Pseudoceratina purpurea that inhibits DNMTs as well as histone deacetylases (McCulloch et al, 2009). Increasing attention is being paid not only to research on drugs that modify the DNA methylation landscape, but also to developing drugs that affect histone modifications.…”