Supercomputer-Based Virtual Screening for Deoxyribonucleic Acid Methyltransferase 1 Inhibitors as Novel Anticancer Agents

Targeting epigenetics is a new strategy to treat cancer and develop novel epigenetic drugs with anti-tumor activity. DNA methyltransferases transfer the methyl group from <i>S</i>-adenosyl-L-methionine (SAM) to the cytosine residue in a CpG island, leading to the transcription silencing of the gene. Hypermethylation can frequently be observed in several tumor types. Hence, the inhibition of DNMT1 has become a novel approach to cure cancer. In this study, virtual screening and molecular docking were performed for more than 11,000 ligands from the ZINC15 database to discover new hypomethylation agents. Four candidate compounds were further tested for their effects on DNMT1 in silico and in vitro. Compounds <b>2</b> and <b>4</b> showed the best DNMT1 inhibitory activity, but only compound <b>4</b> was able to inhibit the growth of several cancer cell lines. The hypomethylation of the luciferase gene by compound <b>4</b> was verified by a <i>CMV</i>- luciferase assay using KG-1 cells. Additionally, compound <b>4</b> suppressed cell migration in a dose- and time-dependent manner in the wound healing assay. Moreover, cell cycle analyses demonstrated that compound <b>4</b> arrested CCRF-CEM cells and MDA-MB-468 cells in the G0/G1 phase. Also, compound <b>4</b> significantly induced early and late apoptosis in a dose-dependent manner. In conclusion, we introduce compound <b>4</b> as a novel DNMT1 inhibitor with anticancer activity.