Abstract：
DNA methylation can deactivate tumor suppressor genes thus causing cancers. Two DNA methylation inhibitors have been approved by the Food and Drug Administration (FDA) and have entered clinical use. However, these inhibitors are nucleoside analogues that can be incorporated into DNA or RNA and induce significant side effects. DNMT1 and DNMT3 are key enzymes involved in DNA methylation. In the acute myeloid leukemia model, a non-nucleoside DNMT1-specific inhibitor has shown lower toxicity and improved pharmacokinetics compared to traditional nucleoside drugs. DNMT3 is also implicated in certain specific cancers. Thus, developing non-nucleoside inhibitors for DNMT1 or DNMT3 can help in understanding their roles in carcinogenesis and provide targeted treatment options in certain cancers. Although no non-nucleoside inhibitors have yet entered clinical trials, in this review, we focus on DNMT1 or DNMT3 selective inhibitors. For DNMT1 selective inhibitors, we have compiled information on the repurposed drugs, derivative compounds and selective inhibitors identified through virtual screening. Additionally, we have outlined potential targets for DNMT1, including protein-protein complex, RNA mimics and aptamers. Compared to DNMT1, research on DNMT3-specific inhibitors has been less extensive. In this context, our exploration has identified a limited number of molecular inhibitors, and we have proposed specific long non-coding RNAs (lncRNAs) as potential contributors to the selective inhibition of DNMT3. This collective effort aims to offer valuable insights into the development of non-nucleoside inhibitors that selectively target DNMT1 or DNMT3.
摘要：
DNA甲基化可以使肿瘤抑制基因失活，从而导致癌症。两种DNA甲基化抑制剂已获得美国食品和药物管理局(FDA)批准并进入临床使用。然而,这些抑制剂是核苷类似物，可以掺入DNA或RNA中并诱导明显的副作用。DNMT1和DNMT3是参与DNA甲基化的关键酶。在急性髓系白血病模型中,与传统核苷类药物相比,非核苷类DNMT1特异性抑制剂显示出更低的毒性和改善的药代动力学.DNMT3也与某些特定癌症有关。因此，开发DNMT1或DNMT3的非核苷抑制剂可以帮助理解它们在癌变中的作用，并为某些癌症提供靶向治疗选择。虽然目前还没有非核苷类抑制剂进入临床试验,在这次审查中,我们专注于DNMT1或DNMT3选择性抑制剂。对于DNMT1选择性抑制剂，我们已经收集了重新利用药物的信息，通过虚拟筛选鉴定的衍生化合物和选择性抑制剂。此外,我们已经概述了DNMT1的潜在靶标，包括蛋白质-蛋白质复合物，RNA模拟物和适体。与DNMT1相比，DNMT3特异性抑制剂的研究还不那么广泛。在这种情况下，我们的探索已经确定了有限数量的分子抑制剂，我们已经提出了特定的长链非编码RNA（lncRNA）作为DNMT3选择性抑制的潜在贡献者。这项集体努力旨在为选择性靶向DNMT1或DNMT3的非核苷抑制剂的开发提供有价值的见解。
